Mony JT, Schuchert MJ. Prognostic implications of heterogeneity in intra-tumoral immune composition for recurrence in early stage lung cancer. Front Immunol. 2018. https://doi.org/10.3389/fimmu.2018.02298.
Google Scholar
Fraire AE, Roggli VL, Vollmer RT, Greenberg SD, Mcgavran MH, Spjut HJ, et al. Lung-cancer heterogeneity – prognostic implications. Cancer-Am Cancer Soc. 1987;60(3):370–5.
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49.
Google Scholar
Oser MG, Niederst MJ, Sequist LV, Engelman JA. Transformation from non-small-cell lung cancer to small-cell lung cancer: molecular drivers and cells of origin. Lancet Oncol. 2015;16(4):e165-172.
Google Scholar
Travis WD, Brambilla E, Nicholson AG, Yatabe Y, Austin JHM, Beasley MB, et al. The 2015 World Health Organization classification of lung tumors: impact of genetic, clinical and radiologic advances since the 2004 classification. J Thorac Oncol. 2015;10(9):1243–60.
Google Scholar
Wang P, Zou J, Wu J, Zhang C, Ma C, Yu J, et al. Clinical profiles and trend analysis of newly diagnosed lung cancer in a tertiary care hospital of East China during 2011–2015. J Thorac Dis. 2017;9(7):1973–9.
Google Scholar
Halliday PR, Blakely CM, Bivona TG. Emerging targeted therapies for the treatment of non-small cell lung cancer. Curr Oncol Rep. 2019;21(3):21.
Google Scholar
Herbst RS, Morgensztern D, Boshoff C. The biology and management of non-small cell lung cancer. Nature. 2018;553(7689):446–54.
Google Scholar
Xie S, Wu Z, Qi Y, Wu B, Zhu X. The metastasizing mechanisms of lung cancer: recent advances and therapeutic challenges. Biomed Pharmacother. 2021;138:111450.
Google Scholar
Xu L, Li HG, Xu ZY, Wang ZQ, Liu LS, Tian JH, et al. Multi-center randomized double-blind controlled clinical study of chemotherapy combined with or without traditional Chinese medicine on quality of life of postoperative non-small cell lung cancer patients. BMC Complement Altern Med. 2012. https://doi.org/10.1186/1472-6882-12-112.
Google Scholar
Gandhi L, Rodriguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, et al. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. New Engl J Med. 2018;378(22):2078–92.
Google Scholar
Fujimoto D, Miura S, Tomii K, Sumikawa H, Yoshimura K, Wakuda K, et al. Pneumonitis associated with pembrolizumab plus chemotherapy for non-squamous non-small cell lung cancer. Sci Rep. 2023. https://doi.org/10.1038/s41598-023-30676-y.
Google Scholar
Hockenhull K, Ortega-Franco A, Califano R. Pembrolizumab plus platinum-based chemotherapy for squamous non-small cell lung cancer: the new kid on the block. Transl Lung Cancer Res. 2021;10(9):3850–4.
Google Scholar
Tang M, Abbas HA, Negrao MV, Ramineni M, Hu X, Hubert SM, et al. The histologic phenotype of lung cancers is associated with transcriptomic features rather than genomic characteristics. Nat Commun. 2021. https://doi.org/10.1038/s41467-021-27341-1.
Google Scholar
Wu F, Fan J, He Y, Xiong A, Yu J, Li Y, et al. Single-cell profiling of tumor heterogeneity and the microenvironment in advanced non-small cell lung cancer. Nat Commun. 2021;12(1):2540.
Google Scholar
Zito Marino F, Bianco R, Accardo M, Ronchi A, Cozzolino I, Morgillo F, et al. Molecular heterogeneity in lung cancer: from mechanisms of origin to clinical implications. Int J Med Sci. 2019;16(7):981–9.
Google Scholar
Fatima S, Kumar V, Kumar D. Molecular mechanism of genetic, epigenetic, and metabolic alteration in lung cancer. Med Oncol. 2025;42(3):61.
Google Scholar
Nicholson AG, Tsao MS, Beasley MB, Borczuk AC, Brambilla E, Cooper WA, et al. The 2021 WHO classification of lung tumors: impact of advances since 2015. J Thorac Oncol. 2022;17(3):362–87.
Google Scholar
Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med. 2008;359(13):1367–80.
Google Scholar
Planchard D, Popat S, Kerr K, Novello S, Smit EF, Faivre-Finn C, et al. Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up (vol 29, pg iv192, 2018). Ann Oncol. 2019;30(5):863–70.
Google Scholar
Denisenko TV, Budkevich IN, Zhivotovsky B. Cell death-based treatment of lung adenocarcinoma. Cell Death Dis. 2018;9(2):117.
Google Scholar
Travis WD, Garg K, Franklin WA, Wistuba II, Sabloff B, Noguchi M, et al. Bronchioloalveolar carcinoma and lung adenocarcinoma: the clinical importance and research relevance of the 2004 World Health Organization pathologic criteria. J Thorac Oncol. 2006;1(9 Suppl):S13-19.
Google Scholar
Moran CA. Pulmonary adenocarcinoma: the expanding spectrum of histologic variants. Arch Pathol Lab Med. 2006;130(7):958–62.
Google Scholar
Yousem SA, Beasley MB. Bronchioloalveolar carcinoma: a review of current concepts and evolving issues. Arch Pathol Lab Med. 2007;131(7):1027–32.
Google Scholar
Moro-Sibilot D, Lantuejoul S, Diab S, Moulai N, Aubert A, Timsit JF, et al. Lung carcinomas with a basaloid pattern: a study of 90 cases focusing on their poor prognosis. Eur Respir J. 2008;31(4):854–9.
Google Scholar
Blandin Knight S, Crosbie PA, Balata H, Chudziak J, Hussell T, Dive C. Progress and prospects of early detection in lung cancer. Open Biol. 2017. https://doi.org/10.1098/rsob.170070.
Google Scholar
Romeo HE, Barreiro Arcos ML. Clinical relevance of stem cells in lung cancer. World J Stem Cells. 2023;15(6):576–88.
Google Scholar
Tsao MS, Nicholson AG, Maleszewski JJ, Marx A, Travis WD. Introduction to 2021 WHO classification of thoracic tumors. J Thorac Oncol. 2022;17(1):E1–4.
Google Scholar
Travis WD, Linnoila RI, Tsokos MG, Hitchcock CL, Cutler GB Jr., Nieman L, et al. Neuroendocrine tumors of the lung with proposed criteria for large-cell neuroendocrine carcinoma. An ultrastructural, immunohistochemical, and flow cytometric study of 35 cases. Am J Surg Pathol. 1991;15(6):529–53.
Google Scholar
Pikor LA, Ramnarine VR, Lam S, Lam WL. Genetic alterations defining NSCLC subtypes and their therapeutic implications. Lung Cancer. 2013;82(2):179–89.
Google Scholar
Thunnissen E, Kerr KM, Herth FJ, Lantuejoul S, Papotti M, Rintoul RC, et al. The challenge of NSCLC diagnosis and predictive analysis on small samples. Practical approach of a working group. Lung Cancer. 2012;76(1):1–18.
Google Scholar
Davidson MR, Gazdar AF, Clarke BE: The pivotal role of pathology in the management of lung cancer. J Thorac Dis. 2013; (Suppl 5):S463–478.
Langer CJ, Besse B, Gualberto A, Brambilla E, Soria JC. The evolving role of histology in the management of advanced non-small-cell lung cancer. J Clin Oncol. 2010;28(36):5311–20.
Google Scholar
Terry J, Leung S, Laskin J, Leslie KO, Gown AM, Ionescu DN. Optimal immunohistochemical markers for distinguishing lung adenocarcinomas from squamous cell carcinomas in small tumor samples. Am J Surg Pathol. 2010;34(12):1805–11.
Google Scholar
Hallack Neto AE, Siqueira SA, Dulley FL, Ruiz MA, Chamone DA, Pereira J. P63 protein expression in high risk diffuse large B-cell lymphoma. J Clin Pathol. 2009;62(1):77–9.
Google Scholar
Bishop JA, Teruya-Feldstein J, Westra WH, Pelosi G, Travis WD, Rekhtman N. P40 (ΔNp63) is superior to p63 for the diagnosis of pulmonary squamous cell carcinoma. Mod Pathol. 2012;25(3):405–15.
Google Scholar
Loo PS, Thomas SC, Nicolson MC, Fyfe MN, Kerr KM. Subtyping of undifferentiated non-small cell carcinomas in bronchial biopsy specimens. J Thorac Oncol. 2010;5(4):442–7.
Google Scholar
Gruver AM, Amin MB, Luthringer DJ, Westfall D, Arora K, Farver CF, et al. Selective immunohistochemical markers to distinguish between metastatic high-grade urothelial carcinoma and primary poorly differentiated invasive squamous cell carcinoma of the lung. Arch Pathol Lab Med. 2012;136(11):1339–46.
Google Scholar
Zhan C, Yan L, Wang L, Sun Y, Wang X, Lin Z, et al. Identification of immunohistochemical markers for distinguishing lung adenocarcinoma from squamous cell carcinoma. J Thorac Dis. 2015;7(8):1398–405.
Google Scholar
Xiao J, Lu X, Chen X, Zou Y, Liu A, Li W, et al. Eight potential biomarkers for distinguishing between lung adenocarcinoma and squamous cell carcinoma. Oncotarget. 2017;8(42):71759.
Google Scholar
Travis WD, Al Dayel FH, Bubendorf L, Chung J-H, Rekhtman N, Scagliotti G: WHO Classification of Tumours, 5th edition: Thoracic Tumours, vol. 5, 5th edn. Lyon, France: International Agency for Research on Cancer; 2021.
Hirsch FR, Suda K, Wiens J, Bunn PA Jr. New and emerging targeted treatments in advanced non-small-cell lung cancer. Lancet. 2016;388(10048):1012–24.
Google Scholar
Murphy SJ, Harris FR, Kosari F, Barreto Siqueira Parrilha Terra S, Nasir A, Johnson SH, et al. Using genomics to differentiate multiple primaries from metastatic lung cancer. J Thorac Oncol. 2019;14(9):1567–82.
Google Scholar
Shen C, Wang X, Tian L, Che G. Microsatellite alteration in multiple primary lung cancer. J Thorac Dis. 2014;6(10):1499–505.
Google Scholar
Wang X, Wang M, MacLennan GT, Abdul-Karim FW, Eble JN, Jones TD, et al. Evidence for common clonal origin of multifocal lung cancers. J Natl Cancer Inst. 2009;101(8):560–70.
Google Scholar
Girard N, Deshpande C, Lau C, Finley D, Rusch V, Pao W, et al. Comprehensive histologic assessment helps to differentiate multiple lung primary nonsmall cell carcinomas from metastases. Am J Surg Pathol. 2009;33(12):1752–64.
Google Scholar
van Rens MT, Eijken EJ, Elbers JR, Lammers JW, Tilanus MG, Slootweg PJ. p53 mutation analysis for definite diagnosis of multiple primary lung carcinoma. Cancer-Am Cancer Soc. 2002;94(1):188–96.
Chang JC, Rekhtman N. Pathologic assessment and staging of multiple non-small cell lung carcinomas: a paradigm shift with the emerging role of molecular methods. Mod Pathol. 2024;37(5):100453.
Google Scholar
Oxnard GR, Binder A, Janne PA. New targetable oncogenes in non-small-cell lung cancer. J Clin Oncol. 2013;31(8):1097–104.
Google Scholar
Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, Cibulskis K, et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature. 2008;455(7216):1069–75.
Google Scholar
Sun S, Schiller JH, Gazdar AF. Lung cancer in never smokers – a different disease. Nat Rev Cancer. 2007;7(10):778–90.
Google Scholar
Tripathi V, Khare A, Shukla D, Bharadwaj S, Kirtipal N, Ranjan V. Genomic and computational-aided integrative drug repositioning strategy for EGFR and ROS1 mutated NSCLC. Int Immunopharmacol. 2024;139:112682.
Google Scholar
Pao W, Girard N. New driver mutations in non-small-cell lung cancer. Lancet Oncol. 2011;12(2):175–80.
Google Scholar
Penzel R, Sers C, Chen Y, Lehmann-Muhlenhoff U, Merkelbach-Bruse S, Jung A, et al. EGFR mutation detection in NSCLC–assessment of diagnostic application and recommendations of the German panel for mutation testing in NSCLC. Virchows Arch. 2011;458(1):95–8.
Google Scholar
Calles A, Sholl LM, Rodig SJ, Pelton AK, Hornick JL, Butaney M, et al. Immunohistochemical loss of LKB1 is a biomarker for more aggressive biology in KRAS-mutant lung adenocarcinoma. Clin Cancer Res. 2015;21(12):2851–60.
Google Scholar
Skoulidis F, Heymach JV. Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy. Nat Rev Cancer. 2019;19(9):495–509.
Google Scholar
Fernandez-Cuesta L, Plenker D, Osada H, Sun R, Menon R, Leenders F, et al. CD74-NRG1 fusions in lung adenocarcinoma. Cancer Discov. 2014;4(4):415–22.
Google Scholar
Kohno T, Ichikawa H, Totoki Y, Yasuda K, Hiramoto M, Nammo T, et al. KIF5B-RET fusions in lung adenocarcinoma. Nat Med. 2012;18(3):375–7.
Google Scholar
Rikova K, Guo A, Zeng Q, Possemato A, Yu J, Haack H, et al. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell. 2007;131(6):1190–203.
Google Scholar
Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448(7153):561–6.
Google Scholar
Stephens P, Hunter C, Bignell G, Edkins S, Davies H, Teague J, et al. Lung cancer: intragenic ERBB2 kinase mutations in tumours. Nature. 2004;431(7008):525–6.
Google Scholar
Vaishnavi A, Capelletti M, Le AT, Kako S, Butaney M, Ercan D, et al. Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer. Nat Med. 2013;19(11):1469–72.
Google Scholar
Weiss J, Sos ML, Seidel D, Peifer M, Zander T, Heuckmann JM, et al. Frequent and focal FGFR1 amplification associates with therapeutically tractable FGFR1 dependency in squamous cell lung cancer. Sci Transl Med. 2010;2(62):62ra93.
Google Scholar
Ju YS, Lee WC, Shin JY, Lee S, Bleazard T, Won JK, et al. A transforming KIF5B and RET gene fusion in lung adenocarcinoma revealed from whole-genome and transcriptome sequencing. Genome Res. 2012;22(3):436–45.
Google Scholar
Gold KA. ROS1-targeting the one percent in lung cancer. N Engl J Med. 2014;371(21):2030–1.
Google Scholar
Bergethon K, Shaw AT, Ou SH, Katayama R, Lovly CM, McDonald NT, et al. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol. 2012;30(8):863–70.
Google Scholar
Imielinski M, Berger AH, Hammerman PS, Hernandez B, Pugh TJ, Hodis E, et al. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell. 2012;150(6):1107–20.
Google Scholar
Heist RS, Engelman JA. Snapshot: non-small cell lung cancer. Cancer Cell. 2012;21(3):448–448.
Google Scholar
Network CGAR. Comprehensive genomic characterization of squamous cell lung cancers The Cancer Genome Atlas Research Network (vol 489, pg 519, 2012). Nature. 2012;491(7423):288–288.
Google Scholar
Guagnano V, Kauffmann A, Wohrle S, Stamm C, Ito M, Barys L, et al. FGFR genetic alterations predict for sensitivity to NVP-BGJ398, a selective pan-FGFR inhibitor. Cancer Discov. 2012;2(12):1118–33.
Google Scholar
Kris MG, Johnson BE, Berry LD, Kwiatkowski DJ, Iafrate AJ, Wistuba II, et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA. 2014;311(19):1998–2006.
Google Scholar
Wang Y, Safi M, Hirsch FR, Lu S, Peters S, Govindan R, et al. Immunotherapy for advanced-stage squamous cell lung cancer: the state of the art and outstanding questions. Nat Rev Clin Oncol. 2025. https://doi.org/10.1038/s41571-024-00979-8.
Google Scholar
Liu L, Bai X, Wang J, Tang XR, Wu DH, Du SS, et al. Combination of TMB and CNA stratifies prognostic and predictive responses to immunotherapy across metastatic cancer. Clin Cancer Res. 2019;25(24):7413–23.
Google Scholar
Hutchinson L. Biomarkers: aneuploidy and immune evasion – a biomarker of response. Nat Rev Clin Oncol. 2017;14(3):140.
Google Scholar
Franco R, Rocco G, Marino FZ, Pirozzi G, Normanno N, Morabito A, et al. Anaplastic lymphoma kinase: a glimmer of hope in lung cancer treatment? Expert Rev Anticancer Ther. 2013;13(4):407–20.
Google Scholar
Lindeman NI, Cagle PT, Aisner DL, Arcila ME, Beasley MB, Bernicker EH, et al. Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: guideline from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. Arch Pathol Lab Med. 2018;142(3):321–46.
Google Scholar
Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304(5676):1497–500.
Google Scholar
Salgia R. MET in lung cancer: biomarker selection based on scientific rationale. Mol Cancer Ther. 2017;16(4):555–65.
Google Scholar
Jin G, Kim MJ, Jeon HS, Choi JE, Kim DS, Lee EB, et al. PTEN mutations and relationship to EGFR, ERBB2, KRAS, and TP53 mutations in non-small cell lung cancers. Lung Cancer. 2010;69(3):279–83.
Google Scholar
Kandoth C, McLellan MD, Vandin F, Ye K, Niu BF, Lu C, et al. Mutational landscape and significance across 12 major cancer types. Nature. 2013;502(7471):333.
Google Scholar
Engelman JA, Chen L, Tan X, Crosby K, Guimaraes AR, Upadhyay R, et al. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med. 2008;14(12):1351–6.
Google Scholar
Mitsudomi T, Hamajima N, Ogawa M, Takahashi T. Prognostic significance of p53 alterations in patients with non-small cell lung cancer: a meta-analysis. Clin Cancer Res. 2000;6(10):4055–63.
Google Scholar
Li BT, Ross DS, Aisner DL, Chaft JE, Hsu M, Kako SL, et al. HER2 amplification and HER2 mutation are distinct molecular targets in lung cancers. J Thorac Oncol. 2016;11(3):414–9.
Google Scholar
Fiala O, Pesek M, Finek J, Minarik M, Benesova L, Sorejs O, et al. Epidermal growth factor receptor gene amplification in patients with advanced-stage NSCLC. Anticancer Res. 2016;36(1):455–60.
Google Scholar
Zhu CQ, Cutz JC, Liu N, Lau D, Shepherd FA, Squire JA, et al. Amplification of telomerase (hTERT) gene is a poor prognostic marker in non-small-cell lung cancer. Br J Cancer. 2006;94(10):1452–9.
Google Scholar
Lou-Qian Z, Rong Y, Ming L, Xin Y, Feng J, Lin X. The prognostic value of epigenetic silencing of p16 gene in NSCLC patients: a systematic review and meta-analysis. PLoS ONE. 2013;8(1):e54970.
Google Scholar
Marek L, Ware KE, Fritzsche A, Hercule P, Helton WR, Smith JE, et al. Fibroblast growth factor (FGF) and FGF receptor-mediated autocrine signaling in non-small-cell lung cancer cells. Mol Pharmacol. 2009;75(1):196–207.
Google Scholar
Hammerman PS, Sos ML, Ramos AH, Xu CX, Dutt A, Zhou WJ, et al. Mutations in the DDR2 kinase gene identify a novel therapeutic target in squamous cell lung cancer. Cancer Discov. 2011;1(1):78–89.
Google Scholar
Paik PK, Arcila ME, Fara M, Sima CS, Miller VA, Kris MG, et al. Clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations. J Clin Oncol. 2011;29(15):2046–51.
Google Scholar
Mascaux C, Iannino N, Martin B, Paesmans M, Berghmans T, Dusart M, et al. The role of RAS oncogene in survival of patients with lung cancer: a systematic review of the literature with meta-analysis. Br J Cancer. 2005;92(1):131–9.
Google Scholar
Kawano O, Sasaki H, Endo K, Suzuki E, Haneda H, Yukiue H, et al. PIK3CA mutation status in Japanese lung cancer patients. Lung Cancer. 2006;54(2):209–15.
Google Scholar
Bass AJ, Watanabe H, Mermel CH, Yu SY, Perner S, Verhaak RG, et al. SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas. Nat Genet. 2009;41(11):1238-U1105.
Google Scholar
Soria JC, Lee HY, Lee JI, Wang L, Issa JP, Kemp BL, et al. Lack of PTEN expression in non-small cell lung cancer could be related to promoter methylation. Clin Cancer Res. 2002;8(5):1178–84.
Google Scholar
Yamazaki M, Hosokawa M, Matsunaga H, Arikawa K, Takamochi K, Suzuki K, et al. Integrated spatial analysis of gene mutation and gene expression for understanding tumor diversity in formalin-fixed paraffin-embedded lung adenocarcinoma. Front Oncol. 2022;12:936190.
Google Scholar
Garber ME, Troyanskaya OG, Schluens K, Petersen S, Thaesler Z, Pacyna-Gengelbach M, et al. Diversity of gene expression in adenocarcinoma of the lung. Proc Natl Acad Sci U S A. 2001;98(24):13784–9.
Google Scholar
Sun ZF, Yang P, Aubry MC, Kosari F, Endo C, Molina J, Vasmatzis G: Can gene expression profiling predict survival for patients with squamous cell carcinoma of the lung? Mol Cancer. 2004; 3(1):35
Beer DG, Kardia SLR, Huang CC, Giordano TJ, Levin AM, Misek DE, et al. Gene-expression profiles predict survival of patients with lung adenocarcinoma. Nat Med. 2002;8(8):816–24.
Google Scholar
Wilkerson MD, Yin X, Hoadley KA, Liu Y, Hayward MC, Cabanski CR, et al. Lung squamous cell carcinoma mRNA expression subtypes are reproducible, clinically important, and correspond to normal cell types. Clin Cancer Res. 2010;16(19):4864–75.
Google Scholar
Cancer Genome Atlas Research N: Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014; 511(7511):543.
Dong JS, Li BJ, Lin D, Zhou QH, Huang DP: Advances in Targeted Therapy and Immunotherapy for Non-small Cell Lung Cancer Based on Accurate Molecular Typing. Front Pharmacol. 2019; 10:230
Ettinger DS, Wood DE, Aisner DL, Akerley W, Bauman JR, Bharat A, et al. NCCN guidelines insights: non–small cell lung cancer, version 2.2021: featured updates to the NCCN guidelines. J Natl Compr Canc Netw. 2021;19(3):254–66.
Google Scholar
Hendriks LE, Kerr KM, Menis J, Mok TS, Nestle U, Passaro A, et al. Oncogene-addicted metastatic non-small-cell lung cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023;34(4):339–57.
Google Scholar
Takeuchi K, Choi YL, Soda M, Inamura K, Togashi Y, Hatano S, et al. Multiplex reverse transcription-PCR screening for EML4-ALK fusion transcripts. Clin Cancer Res. 2008;14(20):6618–24.
Google Scholar
Wong DWS, Leung ELH, Kam-Ting K, Tam IYS, Sihoe ADL, Cheng LC, et al. The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS. Cancer-Am Cancer Soc. 2009;115(8):1723–33.
Shaw AT, Solomon B. Targeting anaplastic lymphoma kinase in lung cancer. Clin Cancer Res. 2011;17(8):2081–6.
Google Scholar
Solomon B, Varella-Garcia M, Camidge DR. ALK gene rearrangements: a new therapeutic target in a molecularly defined subset of non-small cell lung cancer. J Thorac Oncol. 2009;4(12):1450–4.
Google Scholar
Fontana E, Valeri N. Class(y) dissection of BRAF heterogeneity: beyond non-V600. Clin Cancer Res. 2019;25(23):6896–8.
Google Scholar
Tabbo F, Pisano C, Mazieres J, Mezquita L, Nadal E, Planchard D, et al. How far we have come targeting BRAF-mutant non-small cell lung cancer (NSCLC). Cancer Treat Rev. 2022. https://doi.org/10.1016/j.ctrv.2021.102335.
Google Scholar
Dagogo-Jack I, Martinez P, Yeap BY, Ambrogio C, Ferris LA, Lydon C, et al. Impact of BRAF mutation class on disease characteristics and clinical outcomes in BRAF-mutant lung cancer. Clin Cancer Res. 2019;25(1):158–65.
Google Scholar
Murciano-Goroff YR, Pak T, Mondaca S, Flynn JR, Montecalvo J, Rekhtman N, et al. Immune biomarkers and response to checkpoint inhibition of BRAF(V600) and BRAF non-V600 altered lung cancers. Br J Cancer. 2022;126(6):889–98.
Google Scholar
Chen D, Zhang LQ, Huang JF, Liu K, Chuai ZR, Yang Z, et al. BRAF mutations in patients with non-small cell lung cancer: a systematic review and meta-analysis. PLoS ONE. 2014;9(6):e101354.
Google Scholar
O’Leary CG, Andelkovic V, Ladwa R, Pavlakis N, Zhou C, Hirsch F, et al. Targeting BRAF mutations in non-small cell lung cancer. Transl Lung Cancer Res. 2019;8(6):1119–24.
Google Scholar
Provencio M, Molina MA, Rosell R: Screening for Epidermal Growth Factor Receptor Mutations in Lung Cancer and Tyrosine-Kinase Inhibitors. Eur J Clin Med Oncology 2011, 3(2 ) p42
Rosell R, Moran T, Queralt C, Porta R, Cardenal F, Camps C, et al. Screening for Epidermal Growth Factor Receptor Mutations in Lung Cancer. New Engl J Med. 2009;361(10):958-U938.
Google Scholar
Yang G, Li J, Xu H, Yang Y, Yang L, Xu F, et al. EGFR exon 20 insertion mutations in Chinese advanced non-small cell lung cancer patients: molecular heterogeneity and treatment outcome from nationwide real-world study. Lung Cancer. 2020;145:186–94.
Google Scholar
Heist RS, Mino-Kenudson M, Sequist LV, Tammireddy S, Morrissey L, Christiani DC, et al. FGFR1 amplification in squamous cell carcinoma of the lung. J Thorac Oncol. 2012;7(12):1775–80.
Google Scholar
Kim HR, Kim DJ, Kang DR, Lee JG, Lim SM, Lee CY, et al. Fibroblast growth factor receptor 1 gene amplification is associated with poor survival and cigarette smoking dosage in patients with resected squamous cell lung cancer. J Clin Oncol. 2013;31(6):731–7.
Google Scholar
Preusser M, Berghoff AS, Berger W, Ilhan-Mutlu A, Dinhof C, Widhalm G, et al. High rate of FGFR1 amplifications in brain metastases of squamous and non-squamous lung cancer. Lung Cancer. 2014;83(1):83–9.
Google Scholar
Wang K, Ji W, Yu Y, Li Z, Niu X, Xia W, et al. FGFR1-ERK1/2-SOX2 axis promotes cell proliferation, epithelial-mesenchymal transition, and metastasis in FGFR1-amplified lung cancer. Oncogene. 2018;37(39):5340–54.
Google Scholar
Guisier F, Dubos-Arvis C, Vinas F, Doubre H, Ricordel C, Ropert S, et al. Efficacy and safety of anti-PD-1 immunotherapy in patients with advanced NSCLC with BRAF, HER2, or MET mutations or RET translocation: GFPC 01–2018. J Thorac Oncol. 2020;15(4):628–36.
Google Scholar
Mazières J, Peters S, Lepage B, Cortot AB, Barlesi F, Beau-Faller M, et al. Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives. J Clin Oncol. 2013;31(16):1997-U1307.
Google Scholar
Cappuzzo F, Bemis L, Varella-Garcia M. HER2 mutation and response to trastuzumab therapy in non-small-cell lung cancer. N Engl J Med. 2006;354(24):2619–21.
Google Scholar
Chu QS. Targeting non-small cell lung cancer: driver mutation beyond epidermal growth factor mutation and anaplastic lymphoma kinase fusion. Ther Adv Med Oncol. 2020;12:1758835919895756.
Google Scholar
Zhao J, Xia Y. Targeting HER2 alterations in non-small-cell lung cancer: a comprehensive review. JCO Precis Oncol. 2020;4:411–25.
Google Scholar
Peters S, Zimmermann S. Targeted therapy in NSCLC driven by HER2 insertions. Transl Lung Cancer Res. 2014;3(2):84–8.
Google Scholar
Calles A, Liao X, Sholl LM, Rodig SJ, Freeman GJ, Butaney M, et al. Expression of PD-1 and its ligands, PD-L1 and PD-L2, in smokers and never smokers with KRAS-mutant lung cancer. J Thorac Oncol. 2015;10(12):1726–35.
Google Scholar
Negrao MV, Skoulidis F, Montesion M, Schulze K, Bara I, Shen V, et al. Oncogene-specific differences in tumor mutational burden, PD-L1 expression, and outcomes from immunotherapy in non-small cell lung cancer. J Immunother Cancer. 2021. https://doi.org/10.1136/jitc-2021-002891.
Google Scholar
Kadara H, Choi M, Zhang J, Parra ER, Rodriguez-Canales J, Gaffney SG, et al. Whole-exome sequencing and immune profiling of early-stage lung adenocarcinoma with fully annotated clinical follow-up (vol 28, pg 75, 2017). Ann Oncol. 2018;29(4):1072–1072.
Google Scholar
Martin P, Leighl NB, Tsao MS, Shepherd FA. Mutations as prognostic and predictive markers in non-small cell lung cancer. J Thorac Oncol. 2013;8(5):530–42.
Google Scholar
Feng Y, Thiagarajan PS, Ma PC. MET signaling: novel targeted inhibition and its clinical development in lung cancer. J Thorac Oncol. 2012;7(2):459–67.
Google Scholar
Liang H, Wang M. MET oncogene in non-small cell lung cancer: mechanism of MET dysregulation and agents targeting the HGF/c-Met axis. Onco Targets Ther. 2020;13:2491–510.
Google Scholar
Solomon JP, Hechtman JF. Detection of NTRK fusions: merits and limitations of current diagnostic platforms. Cancer Res. 2019;79(13):3163–8.
Google Scholar
Farago AF, Taylor MS, Doebele RC, Zhu VW, Kummar S, Spira AI, Boyle TA, Haura EB, Arcila ME, Benayed R et al: Clinicopathologic Features of Non-Small-Cell Lung Cancer Harboring an NTRK Gene Fusion. JCO Precis Oncol. 2018; (2)1-12. .
Doebele RC, Drilon A, Paz-Ares L, Siena S, Shaw AT, Farago AF, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1–2 trials. Lancet Oncol. 2020;21(2):271–82.
Google Scholar
Lazzari C, Pecciarini L, Doglioni C, Pedica F, Gajate AMS, Bulotta A, et al. Case report: EML4::NTRK3 gene fusion in a patient with metastatic lung adenocarcinoma successfully treated with entrectinib. Front Oncol. 2022;12:1038774.
Google Scholar
Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016;375(19):1823–33.
Google Scholar
Lee K, Choi YJ, Kim JS, Kim DS, Lee SY, Shin BK, et al. Association between PD-L1 expression and initial brain metastasis in patients with non-small cell lung cancer and its clinical implications. Thorac Cancer. 2021;12(15):2143–50.
Google Scholar
John N, Schlintl V, Sassmann T, Lindenmann J, Fediuk M, Wurm R, et al. Longitudinal analysis of PD-L1 expression in patients with relapsed NSCLC. J Immunother Cancer. 2024. https://doi.org/10.1136/jitc-2023-008592.
Google Scholar
McGowan M, Hoven AS, Lund-Iversen M, Solberg S, Helland Å, Hirsch FR, et al. PIK3CA mutations as prognostic factor in squamous cell lung carcinoma. Lung Cancer. 2017;103:52–7.
Google Scholar
Song Z, Yu X, Zhang Y. Mutation and prognostic analyses of PIK3CA in patients with completely resected lung adenocarcinoma. Cancer Med. 2016;5(10):2694–700.
Google Scholar
Wang Y, Wang Y, Li J, Li J, Che G. Clinical Significance of PIK3CA Gene in Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis. Biomed Res Int. 2020;2020:3608241.
Google Scholar
Scheffler M, Bos M, Gardizi M, Konig K, Michels S, Fassunke J, et al. PIK3CA mutations in non-small cell lung cancer (NSCLC): genetic heterogeneity, prognostic impact and incidence of prior malignancies. Oncotarget. 2015;6(2):1315–26.
Google Scholar
Offin M, Guo R, Wu SL, Sabari J, Land JD, Ni A, Montecalvo J, Halpenny DF, Buie LW, Pak T. et al, Immunophenotype and Response to Immunotherapy of RET-Rearranged Lung Cancers. JCO Precis Oncol. 2019; ( 3) : 1-8
Takeuchi K, Soda M, Togashi Y, Suzuki R, Sakata S, Hatano S, et al. RET, ROS1 and ALK fusions in lung cancer. Nat Med. 2012;18(3):378–81.
Google Scholar
Drilon A, Wang L, Hasanovic A, Suehara Y, Lipson D, Stephens P, et al. Response to cabozantinib in patients with RET fusion-positive lung adenocarcinomas. Cancer Discov. 2013;3(6):630–5.
Google Scholar
Bronte G, Ulivi P, Verlicchi A, Cravero P, Delmonte A, Crino L. Targeting RET-rearranged non-small-cell lung cancer: future prospects. Lung Cancer (Auckl). 2019;10:27–36.
Google Scholar
Chin LP, Soo RA, Soong R, Ou SH. Targeting ROS1 with anaplastic lymphoma kinase inhibitors: a promising therapeutic strategy for a newly defined molecular subset of non-small-cell lung cancer. J Thorac Oncol. 2012;7(11):1625–30.
Google Scholar
Kim HR, Lim SM, Kim HJ, Hwang SK, Park JK, Shin E, et al. The frequency and impact of ROS1 rearrangement on clinical outcomes in never smokers with lung adenocarcinoma. Ann Oncol. 2013;24(9):2364–70.
Google Scholar
Ou SI, Zhu VW, Nagasaka M. Catalog of 5’ fusion partners in ALK-positive NSCLC circa 2020. JTO Clin Res Rep. 2020;1(1):100015.
Google Scholar
Sehgal K, Patell R, Rangachari D, Costa DB. Targeting ROS1 rearrangements in non-small cell lung cancer with crizotinib and other kinase inhibitors. Transl Cancer Res. 2018;7(Suppl 7):S779–86.
Google Scholar
Marcus AI, Zhou W. LKB1 regulated pathways in lung cancer invasion and metastasis. J Thorac Oncol. 2010;5(12):1883–6.
Google Scholar
Zheng J, Deng Y, Huang B, Chen X. Prognostic implications of STK11 with different mutation status and its relationship with tumor-infiltrating immune cells in non-small cell lung cancer. Front Immunol. 2024;15:1387896.
Google Scholar
Chaffer CL, Weinberg RA. A perspective on cancer cell metastasis. Science. 2011;331(6024):1559–64.
Google Scholar
Gupta GP, Massague J. Cancer metastasis: building a framework. Cell. 2006;127(4):679–95.
Google Scholar
Hatakeyama M, Nozawa H. Hallmarks of cancer: after the next generation. Cancer Sci. 2022;113:885–885.
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.
Google Scholar
Dillekas H, Rogers MS, Straume O. Are 90% of deaths from cancer caused by metastases? Cancer Med. 2019;8(12):5574–6.
Google Scholar
Fares J, Fares MY, Khachfe HH, Salhab HA, Fares Y. Molecular principles of metastasis: a hallmark of cancer revisited. Signal Transduct Target Ther. 2020. https://doi.org/10.1038/s41392-020-0134-x.
Google Scholar
Hay ED. An overview of epithelio-mesenchymal transformation. Acta Anat (Basel). 1995;154(1):8–20.
Google Scholar
Allgayer H, Mahapatra S, Mishra B, Swain B, Saha S, Khanra S, et al. Epithelial-to-mesenchymal transition (EMT) and cancer metastasis: the status quo of methods and experimental models 2025. Mol Cancer. 2025;24(1):167.
Google Scholar
Guan X. Cancer metastases: challenges and opportunities. Acta Pharm Sin B. 2015;5(5):402–18.
Google Scholar
Zambelli A, Biamonti G, Amato A. HGF/c-Met signalling in the tumor microenvironment. Adv Exp Med Biol. 2021;1270:31–44.
Google Scholar
Liu W, Powell CA, Wang Q. Tumor microenvironment in lung cancer-derived brain metastasis. Chin Med J (Engl). 2022;135(15):1781–91.
Google Scholar
Berghmans T, Paesmans M, Sculier JP. Prognostic factors in stage III non-small cell lung cancer: a review of conventional, metabolic and new biological variables. Ther Adv Med Oncol. 2011;3(3):127–38.
Google Scholar
Sher T, Dy GK, Adjei AA. Small cell lung cancer. Mayo Clin Proc. 2008;83(3):355–67.
Google Scholar
Wood SL, Pernemalm M, Crosbie PA, Whetton AD. The role of the tumor-microenvironment in lung cancer-metastasis and its relationship to potential therapeutic targets. Cancer Treat Rev. 2014;40(4):558–66.
Google Scholar
Jamal-Hanjani M, Wilson GA, McGranahan N, Birkbak NJ, Watkins TBK, Veeriah S, et al. Tracking the evolution of non-small-cell lung cancer. N Engl J Med. 2017;376(22):2109–21.
Google Scholar
Jia B, Gong T, Sun BS, Zhang ZF, Zhong DS, Wang CL. Identification of a DNA damage repair gene-related signature for lung squamous cell carcinoma prognosis. Thorac Cancer. 2022;13(8):1143–52.
Google Scholar
Sethi N, Kang YB. Unravelling the complexity of metastasis – molecular understanding and targeted therapies. Nat Rev Cancer. 2011;11(10):735–48.
Google Scholar
Nguyen DX, Bos PD, Massague J. Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer. 2009;9(4):274–84.
Google Scholar
Huang J, Osarogiagbon RU, Giroux DJ, Nishimura KK, Bille A, Cardillo G, Detterbeck F, Kernstine K, Kim HK, Lievens Y et al: The International Association for the Study of Lung Cancer Staging Project for Lung Cancer: Proposals for the Revision of the N Descriptors in the Forthcoming Ninth Edition of the TNM Classification for Lung Cancer. J Thorac Oncol. 2024; 19(5):766–785.
Detterbeck FC. The eighth edition TNM stage classification for lung cancer: what does it mean on main street? J Thorac Cardiovasc Surg. 2018;155(1):356–9.
Google Scholar
Detterbeck FC, Chansky K, Groome P, Bolejack V, Crowley J, Shemanski L, et al. The IASLC lung cancer staging project: methodology and validation used in the development of proposals for revision of the stage classification of NSCLC in the forthcoming (eighth) edition of the TNM classification of lung cancer. J Thorac Oncol. 2016;11(9):1433–46.
Google Scholar
Brierley JD, Gospodarowicz MK, Wittekind C: TNM classification of malignant tumours: John Wiley & Sons; 2017.
Rami-Porta R: Staging Manual in Thoracic Oncology. (No Title) 2016.
Amin MB, Greene FL, Edge SB, Compton CC, Gershenwald JE, Brookland RK, et al. The eighth edition AJCC cancer staging manual: continuing to build a bridge from a population-based to a more “personalized” approach to cancer staging. CA Cancer J Clin. 2017;67(2):93–9.
Google Scholar
Rami-Porta R, Bolejack V, Crowley J, Ball D, Kim J, Lyons G, Rice T, Suzuki K, Thomas CF, Jr., Travis WD et al: The IASLC Lung Cancer Staging Project: Proposals for the Revisions of the T Descriptors in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer. J Thorac Oncol. 2015; 10(7):990–1003.
Asamura H, Chansky K, Crowley J, Goldstraw P, Rusch VW, Vansteenkiste JF, Watanabe H, Wu YL, Zielinski M, Ball D et al: The International Association for the Study of Lung Cancer Lung Cancer Staging Project: Proposals for the Revision of the N Descriptors in the Forthcoming 8th Edition of the TNM Classification for Lung Cancer. J Thorac Oncol 2015; 10(12):1675–1684.
Goldstraw P, Chansky K, Crowley J, Rami-Porta R, Asamura H, Eberhardt WE, et al. The IASLC lung cancer staging project: proposals for revision of the TNM stage groupings in the forthcoming (eighth) edition of the TNM classification for lung cancer. J Thorac Oncol. 2016;11(1):39–51.
Google Scholar
Woodman C, Vundu G, George A, Wilson CM. Applications and strategies in nanodiagnosis and nanotherapy in lung cancer. Semin Cancer Biol. 2021;69:349–64.
Google Scholar
Fong KM, Rosenthal A, Giroux DJ, Nishimura KK, Erasmus J, Lievens Y, Marino M, Marom EM, Putora PM, Singh N et al: The International Association for the Study of Lung Cancer Staging Project for Lung Cancer: Proposals for the Revision of the M Descriptors in the Forthcoming Ninth Edition of the TNM Classification for Lung Cancer. J Thorac Oncol. 2024; 19(5):786–802.
Tsao MS, Rosenthal A, Nicholson AG, Detterbeck F, Eberhardt WEE, Lievens Y, Lim E, Matilla JM, Yatabe Y, Filosso PL et al: The International Association for the Study of Lung Cancer Staging Project: The Database and Proposal for the Revision of the Staging of Pulmonary Neuroendocrine Carcinoma in the Forthcoming Ninth Edition of the TNM Classification for Lung Cancer. J Thorac Oncol. 2025.
Rami-Porta R, Nishimura KK, Giroux DJ, Detterbeck F, Cardillo G, Edwards JG, et al. The International Association for the Study of Lung Cancer Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groups in the Forthcoming (Ninth) Edition of the TNM Classification for Lung Cancer. J Thorac Oncol. 2024;19(7):1007–27.
Google Scholar
Casal-Mourino A, Ruano-Ravina A, Lorenzo-Gonzalez M, Rodriguez-Martinez A, Giraldo-Osorio A, Varela-Lema L, et al. Epidemiology of stage III lung cancer: frequency, diagnostic characteristics, and survival. Transl Lung Cancer Res. 2021;10(1):506–18.
Google Scholar
Walters S, Maringe C, Coleman MP, Peake MD, Butler J, Young N, et al. Lung cancer survival and stage at diagnosis in Australia, Canada, Denmark, Norway, Sweden and the UK: a population-based study, 2004–2007. Thorax. 2013;68(6):551–64.
Google Scholar
Matsuda A, Matsuda T, Shibata A, Katanoda K, Sobue T, Nishimoto H. Japan Cancer Surveillance Research G: Cancer incidence and incidence rates in Japan in 2008: a study of 25 population-based cancer registries for the Monitoring of Cancer Incidence in Japan (MCIJ) project. Jpn J Clin Oncol. 2014;44(4):388–96.
Google Scholar
Little AG, Gay EG, Gaspar LE, Stewart AK. National survey of non-small cell lung cancer in the United States: epidemiology, pathology and patterns of care. Lung Cancer. 2007;57(3):253–60.
Google Scholar
Dunbar KJ, Efe G, Cunningham K, Esquea E, Navaridas R, Rustgi AK. Regulation of metastatic organotropism. Trends Cancer. 2025;11(3):216–31.
Google Scholar
Perisano C, Spinelli MS, Graci C, Scaramuzzo L, Marzetti E, Barone C, et al. Soft tissue metastases in lung cancer: a review of the literature. Eur Rev Med Pharmacol Sci. 2012;16(14):1908–14.
Google Scholar
Quint LE, Tummala S, Brisson LJ, Francis IR, Krupnick AS, Kazerooni EA, et al. Distribution of distant metastases from newly diagnosed non-small cell lung cancer. Ann Thorac Surg. 1996;62(1):246–50.
Google Scholar
Lin HC, Yu CP, Lin HA, Lee HS. A case of lung cancer metastasized to the gastrointestinal anastomosis site where the primary gastric cancer was resected 17 years ago. Lung Cancer. 2011;72(2):255–7.
Google Scholar
Losito NS, Scaffa C, Cantile M, Botti G, Costanzo R, Manna A, et al. Lung cancer diagnosis on ovary mass: a case report. J Ovarian Res. 2013;6(1):34.
Google Scholar
Zhu L, Wang SY, Li SM, Tao L. Metastatic tumors in nasal cavity and pharynx: a clinicopathological analysis of 11 cases. Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2011;46(12):1030–3.
Google Scholar
Peinado H, Zhang HY, Matei IR, Costa-Silva B, Hoshino A, Rodrigues G, et al. Pre-metastatic niches: organ-specific homes for metastases. Nat Rev Cancer. 2017;17(5):302–17.
Google Scholar
Aguado BA, Bushnell GG, Rao SS, Jeruss JS, Shea LD. Engineering the pre-metastatic niche. Nat Biomed Eng. 2017. https://doi.org/10.1038/s41551-017-0077.
Google Scholar
Liu Y, Cao XT. Organotropic metastasis: role of tumor exosomes. Cell Res. 2016;26(2):149–50.
Google Scholar
Hoshino A, Costa-Silva B, Shen TL, Rodrigues G, Hashimoto A, Mark MT, et al. Tumour exosome integrins determine organotropic metastasis. Nature. 2015;527(7578):329.
Google Scholar
Hu Z, Li Z, Ma ZC, Curtis C. Multi-cancer analysis of clonality and the timing of systemic spread in paired primary tumors and metastases. Nat Genet. 2020;52(7):701.
Google Scholar
Hu Z, Curtis C. Looking backward in time to define the chronology of metastasis. Nat Commun. 2020. https://doi.org/10.1038/s41467-020-16995-y.
Google Scholar
Yamada T, Goto Y, Tanaka H, Kimura H, Minato K, Gyotoku H, et al. A phase 2 trial of durvalumab treatment following radiation monotherapy in patients with non-small cell lung cancer ineligible for stage III chemoradiotherapy: the SPIRAL-RT study. Eur J Cancer. 2023. https://doi.org/10.1016/j.ejca.2023.113373.
Google Scholar
Murakami S. Durvalumab for the treatment of non-small cell lung cancer. Expert Rev Anticancer Ther. 2019;19(12):1009–16.
Google Scholar
Robinson SD, Tahir BA, Absalom KAR, Lankathilake A, Das T, Lee C, et al. Radical accelerated radiotherapy for non-small cell lung cancer (NSCLC): a 5-year retrospective review of two dose fractionation schedules. Radiother Oncol. 2020;143:37–43.
Google Scholar
Yin L, Liu X, Shao X, Feng T, Xu J, Wang Q, et al. The role of exosomes in lung cancer metastasis and clinical applications: an updated review. J Transl Med. 2021;19(1):312.
Google Scholar
Shih DJH, Nayyar N, Bihun I, Dagogo-Jack I, Gill CM, Aquilanti E, et al. Genomic characterization of human brain metastases identifies drivers of metastatic lung adenocarcinoma. Nat Genet. 2020;52(4):371–7.
Google Scholar
Zu L, He J, Zhou N, Tang Q, Liang M, Xu S. Identification of multiple organ metastasis-associated hub mRNA/miRNA signatures in non-small cell lung cancer. Cell Death Dis. 2023;14(12):798.
Google Scholar
Sumbly V, Landry I. Unraveling the role of STK11/LKB1 in non-small cell lung cancer. Cureus. 2022;14(1):e21078.
Google Scholar
Friedlaender A, Perol M, Banna GL, Parikh K, Addeo A. Oncogenic alterations in advanced NSCLC: a molecular super-highway. Biomark Res. 2024;12(1):24.
Google Scholar
Lengel HB, Mastrogiacomo B, Connolly JG, Tan KS, Liu Y, Fick CN, Dunne EG, He D, Lankadasari MB, Satravada BA et al: Genomic mapping of metastatic organotropism in lung adenocarcinoma. Cancer Cell. 2023; 41(5):970–985 e973.
Huang Q, Li Y, Huang Y, Wu J, Bao W, Xue C, et al. Advances in molecular pathology and therapy of non-small cell lung cancer. Signal Transduct Target Ther. 2025;10(1):186.
Google Scholar
Myall NJ, Das M. ROS1-rearranged non-small cell lung cancer: understanding biology and optimizing management in the era of new approvals. Curr Probl Cancer. 2024. https://doi.org/10.1016/j.currproblcancer.2024.101133.
Google Scholar
Yatabe Y. Molecular pathology of non-small cell carcinoma. Histopathology. 2024;84(1):50–66.
Google Scholar
Padinharayil H, Varghese J, John MC, Rajanikant GK, Wilson CM, Al-Yozbaki M, et al. Non-small cell lung carcinoma (NSCLC): implications on molecular pathology and advances in early diagnostics and therapeutics. Genes Dis. 2023;10(3):960–89.
Google Scholar
Tamura T, Kurishima K, Nakazawa K, Kagohashi K, Ishikawa H, Satoh H, et al. Specific organ metastases and survival in metastatic non-small-cell lung cancer. Mol Clin Oncol. 2015;3(1):217–21.
Google Scholar
Lengel HB, Mastrogiacomo B, Connolly JG, Tan KS, Liu Y, Fick CN, et al. Genomic mapping of metastatic organotropism in lung adenocarcinoma. Cancer Cell. 2023;41(5):970.
Google Scholar
Lengel H. Genomic mapping of metastatic organotropism: analysis of 2326 primary and organ-specific metastases in lung adenocarcinoma. J Thorac Oncol. 2022;17(9):S62–3.
Google Scholar
Schoenfeld AJ, Bandlamudi C, Lavery JA, Montecalvo J, Namakydoust A, Rizvi H, et al. The genomic landscape of SMARCA4 alterations and associations with outcomes in patients with lung cancer. Clin Cancer Res. 2020;26(21):5701–8.
Google Scholar
Lehtio J, Arslan T, Siavelis I, Pan Y, Socciarelli F, Berkovska O, et al. Proteogenomics of non-small cell lung cancer reveals molecular subtypes associated with specific therapeutic targets and immune evasion mechanisms. Nat Cancer. 2021;2(11):1224–42.
Google Scholar
Concepcion CP, Ma S, LaFave LM, Bhutkar A, Liu M, DeAngelo LP, et al. Smarca4 Inactivation Promotes Lineage-Specific Transformation and Early Metastatic Features in the Lung. Cancer Discov. 2022;12(2):562–85.
Google Scholar
Fernando TM, Piskol R, Bainer R, Sokol ES, Trabucco SE, Zhang Q, et al. Functional characterization of SMARCA4 variants identified by targeted exome-sequencing of 131,668 cancer patients. Nat Commun. 2020;11(1):5551.
Google Scholar
Nguyen B, Fong C, Luthra A, Smith SA, DiNatale RG, Nandakumar S, Walch H, Chatila WK, Madupuri R, Kundra R et al: Genomic characterization of metastatic patterns from prospective clinical sequencing of 25,000 patients. Cell. 2022; 185(3):563–575 e511.
Han G, Bi JP, Tan WY, Wei XY, Wang XH, Ying XF, et al. A retrospective analysis in patients with EGFR-mutant lung adenocarcinoma: is EGFR mutation associated with a higher incidence of brain metastasis? Oncotarget. 2016;7(35):56998–7010.
Google Scholar
Ge M, Zhuang Y, Zhou X, Huang R, Liang X, Zhan Q. High probability and frequency of EGFR mutations in non-small cell lung cancer with brain metastases. J Neurooncol. 2017;135(2):413–8.
Google Scholar
Zhao W, Zhou W, Rong L, Sun M, Lin X, Wang L, et al. Epidermal growth factor receptor mutations and brain metastases in non-small cell lung cancer. Front Oncol. 2022;12:912505.
Google Scholar
Ruiz-Patiño A, Arrieta O, Rojas L, Zuluaga J, Martin C, Corrales L, et al. Molecular and Clonal Evolution of Primary Lesions vs Brain Metastasis and Progressive Disease of EGFR Mutated Patients. J Thorac Oncol. 2024;19(10):S307–8.
Google Scholar
Leung MM, Swanton C, Mcgranahan N. Integrating model systems and genomic insights to decipher mechanisms of cancer metastasis. Nat Rev Genet. 2025;26(7):494–505.
Google Scholar
Al Bakir M, Huebner A, Martínez-Ruiz C, Grigoriadis K, Watkins TBK, Pich O, Moore DA, Veeriah S, Ward S, Laycock J et al: The evolution of non-small cell lung cancer metastases in TRACERx. Nature. 2023; 616(7957):534-+.
Abbosh C, Birkbak NJ, Wilson GA, Jamal-Hanjani M, Constantin T, Salari R, Le Quesne J, Moore DA, Veeriah S, Rosenthal R et al: Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution. Nature. 2017; 545(7655):446-+.
Bailey C, Black JRM, Reading JL, Litchfield K, Turajlic S, McGranahan N, et al. Tracking cancer evolution through the disease course. Cancer Discov. 2021;11(4):916–32.
Google Scholar
Li J, Zhu H, Sun L, Xu W, Wang X. Prognostic value of site-specific metastases in lung cancer: a population based study. J Cancer. 2019;10(14):3079–86.
Google Scholar
Gu Y, Zhang J, Zhou Z, Liu D, Zhu H, Wen J, et al. Metastasis patterns and prognosis of octogenarians with NSCLC: a population-based study. Aging Dis. 2020;11(1):82–92.
Google Scholar
Wang X, Wang Z, Pan J, Lu ZY, Xu D, Zhang HJ, et al. Patterns of Extrathoracic Metastases in Different Histological Types of Lung Cancer. Front Oncol. 2020;10:715.
Google Scholar
Clinical Lung Cancer Genome P, Network Genomic M: A genomics-based classification of human lung tumors. Sci Transl Med. 2013; 5(209):209ra153.
Tan AC, Tan DSW. Targeted therapies for lung cancer patients with oncogenic driver molecular alterations. J Clin Oncol. 2022;40(6):611–25.
Google Scholar
Koban MU, Hartmann M, Amexis G, Franco P, Huggins L, Shah I, et al. Targeted therapies, novel antibodies, and immunotherapies in advanced non-small cell lung cancer: clinical evidence and drug approval patterns. Clin Cancer Res. 2024;30(21):4822–33.
Google Scholar
Drilon A, Wang L, Arcila ME, Balasubramanian S, Greenbowe JR, Ross JS, et al. Broad, hybrid capture–based next-generation sequencing identifies actionable genomic alterations in lung adenocarcinomas otherwise negative for such alterations by other genomic testing approaches. Clin Cancer Res. 2015;21(16):3631–9.
Google Scholar
Shigematsu H, Lin L, Takahashi T, Nomura M, Suzuki M, Wistuba II, et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst. 2005;97(5):339–46.
Google Scholar
Cheng Y, Zhang T, Xu Q: Therapeutic advances in non-small cell lung cancer: Focus on clinical development of targeted therapy and immunotherapy. MedComm (2020). 2021; 2(4):692–729.
Liu GH, Chen T, Zhang X, Ma XL, Shi HS: Small molecule inhibitors targeting the cancers. MedComm (2020). 2022; 3(4):e181.
Makarem M, Janne PA. Top advances of the year: targeted therapy for lung cancer. Cancer-Am Cancer Soc. 2024;130(19):3239–50.
Hendriks LEL, Remon J, Faivre-Finn C, Garassino MC, Heymach JV, Kerr KM, et al. Non-small-cell lung cancer. Nat Rev Dis Primers. 2024;10(1):71.
Google Scholar
Papadimitrakopoulou VA, Mok TS, Han JY, Ahn MJ, Delmonte A, Ramalingam SS, et al. Osimertinib versus platinum-pemetrexed for patients with EGFR T790M advanced NSCLC and progression on a prior EGFR-tyrosine kinase inhibitor: aura3 overall survival analysis. Ann Oncol. 2020;31(11):1536–44.
Google Scholar
Planchard D, Jänne PA, Cheng Y, Yang JCH, Yanagitani N, Kim S-W, et al. Osimertinib with or without chemotherapy in EGFR-mutated advanced NSCLC. N Engl J Med. 2023;389(21):1935–48.
Google Scholar
Cho BC, Lu S, Felip E, Spira AI, Girard N, Lee J-S, et al. Amivantamab plus lazertinib in previously untreated-mutated advanced NSCLC. N Engl J Med. 2024;391(16):1486–98.
Google Scholar
Zhou C, Tang K-J, Cho BC, Liu B, Paz-Ares L, Cheng S, et al. Amivantamab plus chemotherapy in NSCLC with EGFR exon 20 insertions. New Engl J Med. 2023;389(22):2039–51.
Google Scholar
Zhou C, Solomon B, Loong HH, Park K, Pérol M, Arriola E, et al. First-line selpercatinib or chemotherapy and pembrolizumab in RET fusion–positive NSCLC. N Engl J Med. 2023;389(20):1839–50.
Google Scholar
Solomon BJ, Liu G, Felip E, Mok TSK, Soo RA, Mazieres J, et al. Lorlatinib Versus Crizotinib in Patients With Advanced ALK-Positive Non-Small Cell Lung Cancer: 5-Year Outcomes From the Phase III CROWN Study. J Clin Oncol. 2024;42(29):3400–9.
Google Scholar
Shaw AT, Bauer TM, de Marinis F, Felip E, Goto Y, Liu G, et al. First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer. New Engl J Med. 2020;383(21):2018–29.
Google Scholar
Felip E, Shaw AT, Bearz A, Camidge DR, Solomon BJ, Bauman JR, et al. Intracranial and extracranial efficacy of lorlatinib in patients with ALK-positive non-small-cell lung cancer previously treated with second-generation ALK TKIs. Ann Oncol. 2021;32(5):620–30.
Google Scholar
Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature. 2013;503(7477):548–51.
Google Scholar
Skoulidis F, Li BT, Dy GK, Price TJ, Falchook GS, Wolf J, et al. Sotorasib for lung cancers with KRAS p. G12C mutation. N Engl J Med. 2021;384(25):2371–81.
Google Scholar
Jänne PA, Riely GJ, Gadgeel SM, Heist RS. Ou S-HI, Pacheco JM, Johnson ML, Sabari JK, Leventakos K, Yau E: Adagrasib in non–small-cell lung cancer harboring a KRASG12C mutation. New Engl J Med. 2022;387(2):120–31.
Google Scholar
Mok TSK, Yao W, Duruisseaux M, Doucet L, Azkarate Martinez A, Gregorc V, et al. KRYSTAL-12: Phase 3 study of adagrasib versus docetaxel in patients with previously treated advanced/metastatic non-small cell lung cancer (NSCLC) harboring a KRASG12C mutation. In.: American Society of Clinical Oncology; 2024.
De Langen AJ, Johnson ML, Mazieres J. Dingemans A-MC, Mountzios G, Pless M, Wolf J, Schuler M, Lena H, Skoulidis F: Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRASG12C mutation: a randomised, open-label, phase 3 trial. Lancet. 2023;401(10378):733–46.
Google Scholar
Gregorc V, González-Cao M, Salvagni S, Koumarianou A, Gil-Bazo I, Maio M, et al. KROCUS: a phase II study investigating the efficacy and safety of fulzerasib (GFH925) in combination with cetuximab in patients with previously untreated advanced KRAS G12C mutated NSCLC. J Clin Oncol. 2024;42(17_Suppl):Lba8511-Lba8511.
Google Scholar
Chen JY, Lu WJ, Chen M, Cai ZJ, Zhan P, Liu X, et al. Efficacy of immunotherapy in patients with oncogene-driven non-small-cell lung cancer: a systematic review and meta-analysis. Ther Adv Med Oncol. 2024. https://doi.org/10.1177/17588359231225036.
Google Scholar
Chevallier M, Borgeaud M, Addeo A, Friedlaender A. Oncogenic driver mutations in non-small cell lung cancer: past, present and future. World J Clin Oncol. 2021;12(4):217–37.
Google Scholar
Coleman N, Hong L, Zhang J, Heymach J, Hong D, Le X. Beyond epidermal growth factor receptor: MET amplification as a general resistance driver to targeted therapy in oncogene-driven non-small-cell lung cancer. ESMO Open. 2021. https://doi.org/10.1016/j.esmoop.2021.100319.
Google Scholar
Fu K, Xie F, Wang F, Fu L. Therapeutic strategies for EGFR-mutated non-small cell lung cancer patients with osimertinib resistance. J Hematol Oncol. 2022;15(1):173.
Google Scholar
Galffy G, Morocz E, Korompay R, Hecz R, Bujdoso R, Puskas R, et al. Targeted therapeutic options in early and metastatic NSCLC-overview. Pathol Oncol Res. 2024;30:1611715.
Google Scholar
Lara MS, Blakely CM, Riess JW. Targeting MEK in non-small cell lung cancer. Curr Probl Cancer. 2024;49:101065.
Google Scholar
Mountzios G, Saw SPL, Hendriks L, Menis J, Cascone T, Arrieta O, et al. Antibody-drug conjugates in NSCLC with actionable genomic alterations: optimizing smart delivery of chemotherapy to the target. Cancer Treat Rev. 2025;134:102902.
Google Scholar
Heist RS, Guarino MJ, Masters G, Purcell WT, Starodub AN, Horn L, et al. Therapy of advanced non-small-cell lung cancer with an SN-38-anti-Trop-2 drug conjugate. Sacituzumab Govitecan J Clin Oncol. 2017;35(24):2790–7.
Google Scholar
Camidge DR, Morgensztern D, Heist RS, Barve M, Vokes E, Goldman JW, et al. Phase I study of 2-or 3-week dosing of telisotuzumab vedotin, an antibody-drug conjugate targeting c-Met, monotherapy in patients with advanced non-small cell lung carcinoma. Clin Cancer Res. 2021;27(21):5781–92.
Google Scholar
Camidge DR, Barlesi F, Goldman JW, Morgensztern D, Heist R, Vokes E, et al. Phase Ib study of telisotuzumab vedotin in combination with erlotinib in patients with c-Met protein-expressing non-small-cell lung cancer. J Clin Oncol. 2023;41(5):1105–15.
Google Scholar
Goto K, Goto Y, Kubo T, Ninomiya K, Kim S-W, Planchard D, et al. Trastuzumab deruxtecan in patients with HER2-mutant metastatic non–small-cell lung cancer: primary results from the randomized, phase II DESTINY-Lung02 trial. J Clin Oncol. 2023;41(31):4852–63.
Google Scholar
Li BT, Smit EF, Goto Y, Nakagawa K, Udagawa H, Mazières J, et al. Trastuzumab deruxtecan in HER2-mutant non–small-cell lung cancer. N Engl J Med. 2022;386(3):241–51.
Google Scholar
Zhang Q, Chen K, Yu X, Fan Y. Spotlight on the treatment of non-small cell lung cancer with rare genetic alterations and brain metastasis: current status and future perspectives. Int J Cancer. 2024;155(12):2117–28.
Google Scholar
Voruganti T, Marar R, Bleiberg B, Garbo E, Ricciuti B, Parikh K, et al. Perioperative therapy in oncogene-driven non-small cell lung cancer: current strategies and unanswered questions. Am Soc Clin Oncol Educ Book. 2025;45(3):e472804.
Google Scholar
Hendriks LE, Kerr KM, Menis J, Mok TS, Nestle U, Passaro A, et al. Non-oncogene-addicted metastatic non-small-cell lung cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023;34(4):358–76.
Google Scholar
Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med. 2015;373(17):1627–39.
Google Scholar
Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WEE, Poddubskaya E, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. New Engl J Med. 2015;373(2):123–35.
Google Scholar
Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387(10027):1540–50.
Google Scholar
Rittmeyer A, Barlesi F, Waterkamp D. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial (vol 389, pg 255, 2016). Lancet. 2017;389(10077):E5–E5.
Daylan AEC, Halmos B. Long-term benefit of immunotherapy in metastatic non-small cell lung cancer: the tale of the tail. Transl Lung Cancer Res. 2023;12(7):1636–42.
Google Scholar
Mamdani H, Matosevic S, Khalid AB, Durm G, Jalal SI. Immunotherapy in lung cancer: current landscape and future directions. Front Immunol. 2022;13:823618.
Google Scholar
Garon EB, Rizvi NA, Hui RN, Leighl N, Balmanoukian AS, Eder JP, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. New Engl J Med. 2015;372(21):2018–28.
Google Scholar
Herbst RS, Giaccone G, de Marinis F, Reinmuth N, Vergnenegre A, Barrios CH, et al. Atezolizumab for First-Line Treatment of PD-L1-Selected Patients with NSCLC. N Engl J Med. 2020;383(14):1328–39.
Google Scholar
Sezer A, Kilickap S, Gümüş M, Bondarenko I, Özgüroğlu M, Gogishvili M, et al. Cemiplimab monotherapy for first-line treatment of advanced non-small-cell lung cancer with PD-L1 of at least 50%: a multicentre, open-label, global, phase 3, randomised, controlled trial. Lancet. 2021;397(10274):592–604.
Google Scholar
Yang JC-H, Han B, Jiménez EDLM, Lee J-S, Koralewski P, Karadurmus N, et al. Pembrolizumab with or without lenvatinib for first-line metastatic NSCLC with programmed cell death-ligand 1 tumor proportion score of at least 1%(LEAP-007): a randomized, double-blind, phase 3 trial. J Thorac Oncol. 2024;19(6):941–53.
Google Scholar
Boyer M, Sendur MAN, Rodriguez-Abreu D, Park K, Lee DH, Cicin I, et al. Pembrolizumab Plus Ipilimumab or Placebo for Metastatic Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score >/= 50%: Randomized, Double-Blind Phase III KEYNOTE-598 Study. J Clin Oncol. 2021;39(21):2327–38.
Google Scholar
Cho BC, Lee JS, Wu YL, Cicin I, Dols MC, Ahn MJ, et al. Bintrafusp Alfa Versus Pembrolizumab in Patients With Treatment-Naive, Programmed Death-Ligand 1-High Advanced NSCLC: A Randomized, Open-Label, Phase 3 Trial. J Thorac Oncol. 2023;18(12):1731–42.
Google Scholar
Genentech: Genentech Reports Interim Results for Phase III SKYSCRAPER‐01 Study in PD‐L1‐High Metastatic Non‐Small Cell Lung Cancer. 2022.
Reck M, Ciuleanu TE, Cobo M, Schenker M, Zurawski B, Menezes J, et al. First-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone (four cycles) in advanced non-small-cell lung cancer: CheckMate 9LA 2-year update. Esmo Open. 2021;6(5):100273.
Google Scholar
Johnson ML, Cho BC, Luft A, Alatorre-Alexander J, Geater SL, Laktionov K, et al. Durvalumab with or without tremelimumab in combination with chemotherapy as first-line therapy for metastatic non–small-cell lung cancer: the phase III poseidon study. J Clin Oncol. 2023;41(6):1213–27.
Google Scholar
Carbone DP, Ciuleanu TE, Schenker M, Cobo M, Bordenave S, Juan-Vidal O, et al. Four-year clinical update and treatment switching-adjusted outcomes with first-line nivolumab plus ipilimumab with chemotherapy for metastatic non-small cell lung cancer in the CheckMate 9LA randomized trial. J Immunother Cancer. 2024. https://doi.org/10.1136/jitc-2023-008189.
Google Scholar
Ahn MJ, Lisberg A, Paz-Ares L, Cornelissen R, Girard N, Pons-Tostivint E, et al. LBA12 Datopotamab deruxtecan (Dato-DXd) vs docetaxel in previously treated advanced/metastatic (adv/met) non-small cell lung cancer (NSCLC): results of the randomized phase III study TROPION-Lung01. Ann Oncol. 2023;34:S1305–6.
Google Scholar
Paz-Ares LG, Juan-Vidal O, Mountzios GS, Felip E, Reinmuth N, de Marinis F, et al. Sacituzumab govitecan versus docetaxel for previously treated advanced or metastatic non–small cell lung cancer: the randomized, open-label phase III EVOKE-01 study. J Clin Oncol. 2024;42(24):2860–72.
Google Scholar
Lee SM, Schulz C, Prabhash K, Kowalski D, Szczesna A, Han B, et al. First-line atezolizumab monotherapy versus single-agent chemotherapy in patients with non-small-cell lung cancer ineligible for treatment with a platinum-containing regimen (IPSOS): a phase 3, global, multicentre, open-label, randomised controlled study. Lancet. 2023;402(10400):451–63.
Google Scholar
Borghaei H, De Marinis F, Dumoulin D, Reynolds C, Theelen W, Calderon VG, et al. SAPPHIRE: phase III study of sitravatinib plus nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. Ann Oncol. 2024;35(1):66–76.
Google Scholar
Neal J, Pavlakis N, Kim SW, Goto Y, Lim SM, Mountzios G, et al. 60 CONTACT-01: Efficacy and safety from a phase III study of atezolizumab (atezo)+ cabozantinib (cabo) vs docetaxel (doc) monotherapy in patients (pts) with metastatic NSCLC (mNSCLC) previously treated with checkpoint inhibitors and chemotherapy. J Thorac Oncol. 2023;18(4):S39–40.
Google Scholar
Paz-Ares L, Goto Y, Lim WDT, Halmos B, Cho BC, Dols MC, et al. 1194MO Canakinumab (CAN)+ docetaxel (DTX) for the second-or third-line (2/3L) treatment of advanced non-small cell lung cancer (NSCLC): CANOPY-2 phase III results. Ann Oncol. 2021;32:S953–4.
Google Scholar
Besse B, Felip E, Campelo RG, Cobo M, Mascaux C, Madroszyk A, et al. Randomized open-label controlled study of cancer vaccine OSE2101 versus chemotherapy in HLA-A2-positive patients with advanced non-small-cell lung cancer with resistance to immunotherapy: ATALANTE-1. Ann Oncol. 2023;34(10):920–33.
Google Scholar
Morton JJ, Bird G, Refaeli Y, Jimeno A. Humanized mouse xenograft models: narrowing the tumor-microenvironment gap. Cancer Res. 2016;76(21):6153–8.
Google Scholar
Shilts J, Severin Y, Galaway F, Müller-Sienerth N, Chong ZS, Pritchard S, et al. A physical wiring diagram for the human immune system (vol 608, pg 397, 2022). Nature. 2024;635(8037):E1–E1.
Google Scholar
Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009;119(6):1420–8.
Google Scholar
Neelakantan D, Zhou H, Oliphant MUJ, Zhang X, Simon LM, Henke DM, et al. EMT cells increase breast cancer metastasis via paracrine GLI activation in neighbouring tumour cells. Nat Commun. 2017;8:15773.
Google Scholar
Amin A, Alyahyaee M, Xie YQ, Tahtamouni L. Editorial: Molecular mechanisms of epithelial-mesenchymal transition in cancer metastasis. Front Oncol. 2022. https://doi.org/10.3389/fonc.2022.1088205.
Google Scholar
Puisieux A, Brabletz T, Caramel J. Oncogenic roles of EMT-inducing transcription factors. Nat Cell Biol. 2014;16(6):488–94.
Google Scholar
Cano A, Perez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG, et al. The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol. 2000;2(2):76–83.
Google Scholar
Tran PT, Shroff EH, Burns TF, Thiyagarajan S, Das ST, Zabuawala T, et al. Twist1 suppresses senescence programs and thereby accelerates and maintains mutant Kras-induced lung tumorigenesis. PLoS Genet. 2012. https://doi.org/10.1371/journal.pgen.1002650.
Google Scholar
Huang Y, Hong W, Wei X. The molecular mechanisms and therapeutic strategies of EMT in tumor progression and metastasis. J Hematol Oncol. 2022;15(1):129.
Google Scholar
Gonzalez DM, Medici D: Signaling mechanisms of the epithelial-mesenchymal transition. Sci Signal. 2014; 7(344):re8.
Zhang T, Guo L, Creighton CJ, Lu Q, Gibbons DL, Yi ES, et al. A genetic cell context-dependent role for ZEB1 in lung cancer. Nat Commun. 2016;7:12231.
Google Scholar
Thomson S, Buck E, Petti F, Griffin G, Brown E, Ramnarine N, et al. Epithelial to mesenchymal transition is a determinant of sensitivity of non-small-cell lung carcinoma cell lines and xenografts to epidermal growth factor receptor inhibition. Cancer Res. 2005;65(20):9455–62.
Google Scholar
Altorki NK, Markowitz GJ, Gao D, Port JL, Saxena A, Stiles B, et al. The lung microenvironment: an important regulator of tumour growth and metastasis. Nat Rev Cancer. 2019;19(1):9–31.
Google Scholar
Richard G, Dalle S, Monet MA, Ligier M, Boespflug A, Pommier RM, et al. ZEB1-mediated melanoma cell plasticity enhances resistance to MAPK inhibitors. EMBO Mol Med. 2016;8(10):1143–61.
Google Scholar
Deng QD, Lei XP, Zhong YH, Chen MS, Ke YY, Li Z, et al. Triptolide suppresses the growth and metastasis of non-small cell lung cancer by inhibiting beta-catenin-mediated epithelial-mesenchymal transition. Acta Pharmacol Sin. 2021;42(9):1486–97.
Google Scholar
Ceteci F, Ceteci S, Karreman C, Kramer BW, Asan E, Gotz R, et al. Disruption of tumor cell adhesion promotes angiogenic switch and progression to micrometastasis in RAF-driven murine lung cancer. Cancer Cell. 2007;12(2):145–59.
Google Scholar
Richardson AM, Havel LS, Koyen AE, Konen JM, Shupe J, Wiles WG, et al. Vimentin is required for lung adenocarcinoma metastasis via heterotypic tumor cell-cancer associated fibroblast interactions during collective invasion. Clin Cancer Res. 2018;24(2):420–32.
Google Scholar
Manshouri R, Coyaud E, Kundu ST, Peng DH, Stratton SA, Alton K, et al. ZEB1/NuRD complex suppresses TBC1D2b to stimulate E-cadherin internalization and promote metastasis in lung cancer. Nat Commun. 2019;10(1):5125.
Google Scholar
Matsubara D, Kishaba Y, Yoshimoto T, Sakuma Y, Sakatani T, Tamura T, et al. Immunohistochemical analysis of the expression of E-cadherin and ZEB1 in non-small cell lung cancer. Pathol Int. 2014;64(11):560–8.
Google Scholar
Larsen JE, Nathan V, Osborne JK, Farrow RK, Deb D, Sullivan JP, et al. ZEB1 drives epithelial-to-mesenchymal transition in lung cancer. J Clin Invest. 2016;126(9):3219–35.
Google Scholar
Liu X, Li C, Yang Y, Liu X, Li R, Zhang M, et al. Synaptotagmin 7 in twist-related protein 1-mediated epithelial – mesenchymal transition of non-small cell lung cancer. EBioMedicine. 2019;46:42–53.
Google Scholar
Chen LM, Gibbons DL, Goswami S, Cortez MA, Ahn YH, Byers LA, et al. Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression. Nat Commun. 2014. https://doi.org/10.1038/ncomms6241.
Google Scholar
Lei X, Li Z, Zhong Y, Li S, Chen J, Ke Y, et al. Gli1 promotes epithelial-mesenchymal transition and metastasis of non-small cell lung carcinoma by regulating snail transcriptional activity and stability. Acta Pharm Sin B. 2022;12(10):3877–90.
Google Scholar
Evanno E, Godet J, Piccirilli N, Guilhot J, Milin S, Gombert JM, et al. Tri-methylation of H3K79 is decreased in TGF-β1-induced epithelial-to-mesenchymal transition in lung cancer. Clin Epigenetics. 2017. https://doi.org/10.1186/s13148-017-0380-0.
Google Scholar
Asgarova A, Asgarov K, Godet Y, Peixoto P, Nadaradjane A, Boyer-Guittaut M, et al. PD-L1 expression is regulated by both DNA methylation and NF-κB during EMT signaling in non-small cell lung carcinoma. Oncoimmunology. 2018. https://doi.org/10.1080/2162402X.2017.1423170.
Google Scholar
Nakasuka F, Tabata S, Sakamoto T, Hirayama A, Ebi H, Yamada T, et al. TGF-β-dependent reprogramming of amino acid metabolism induces epithelial-mesenchymal transition in non-small cell lung cancers. Commun Biol. 2021. https://doi.org/10.1038/s42003-021-02323-7.
Google Scholar
Zhang S, Che D, Yang F, Chi C, Meng H, Shen J, et al. Tumor-associated macrophages promote tumor metastasis via the TGF-beta/SOX9 axis in non-small cell lung cancer. Oncotarget. 2017;8(59):99801–15.
Google Scholar
Che DH, Zhang S, Jing ZH, Shang LH, Jin S, Liu F, et al. Macrophages induce EMT to promote invasion of lung cancer cells through the IL-6-mediated COX-2/PGE/β-catenin signalling pathway (vol 90, pg 197, 2017). Mol Immunol. 2020;126:165–6.
Google Scholar
Lou YY, Diao LX, Cuentas ERP, Denning WL, Chen LM, Fan YH, et al. Epithelial-mesenchymal transition is associated with a distinct tumor microenvironment including elevation of inflammatory signals and multiple immune checkpoints in lung adenocarcinoma. Clin Cancer Res. 2016;22(14):3630–42.
Google Scholar
Manjunath Y, Upparahalli S, Avella DM, Deroche CB, Kimchi ET, Staveley-O’Carroll KE, Smith CJ, Li GF, Kaifi JT: PD-L1 Expression with Epithelial Mesenchymal Transition of Circulating Tumor Cells Is Associated with Poor Survival in Curatively Resected Non-Small Cell Lung Cancer. Cancers. 2019; 11(6).
Hata AN, Niederst MJ, Archibald HL, Gomez-Caraballo M, Siddiqui FM, Mulvey HE, et al. Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition. Nat Med. 2016;22(3):262–9.
Google Scholar
Wang LM, Cao LM, Wang HM, Liu BN, Zhang QC, Meng ZW, et al. Cancer-associated fibroblasts enhance metastatic potential of lung cancer cells through IL-6/STAT3 signaling pathway. Oncotarget. 2017;8(44):76116–28.
Google Scholar
Groza Y, Lacina L, Kuchar M, Raskova Kafkova L, Zachova K, Janouskova O, et al. Small protein blockers of human IL-6 receptor alpha inhibit proliferation and migration of cancer cells. Cell Commun Signal. 2024;22(1):261.
Google Scholar
Li HB, Zhang Q, Wu Q, Cui YY, Zhu H, Fang MM, et al. Interleukin-22 secreted by cancer-associated fibroblasts regulates the proliferation and metastasis of lung cancer cells via the PI3K-Akt-mTOR signaling pathway. Am J Transl Res. 2019;11(7):4077–88.
Google Scholar
Li JF, Niu YY, Xing YL, Liu F. A novel bispecific c-MET/CTLA-4 antibody targetting lung cancer stem cell-like cells with therapeutic potential in human non-small-cell lung cancer. 2019. Biosci Rep. https://doi.org/10.1042/BSR20171278.
Kuchar M, Sloupenska K, Raskova Kafkova L, Groza Y, Skarda J, Kosztyu P, et al. Human IL-22 receptor-targeted small protein antagonist suppress murine DSS-induced colitis. Cell Commun Signal. 2024;22(1):469.
Google Scholar
Zhou Z, Zhou Q, Wu X, Xu S, Hu XH, Tao XX, et al. VCAM-1 secreted from cancer-associated fibroblasts enhances the growth and invasion of lung cancer cells through AKT and MAPK signaling. Cancer Lett. 2020;473:62–73.
Google Scholar
Guo Z, Song J, Hao J, Zhao H, Du X, Li E, et al. M2 macrophages promote NSCLC metastasis by upregulating CRYAB. Cell Death Dis. 2019;10(6):377.
Google Scholar
Salazar Y, Zheng X, Brunn D, Raifer H, Picard F, Zhang Y, et al. Microenvironmental Th9 and Th17 lymphocytes induce metastatic spreading in lung cancer. J Clin Invest. 2020;130(7):3560–75.
Google Scholar
Zhou Y, Shurin GV, Zhong H, Bunimovich YL, Han B, Shurin MR. Schwann cells augment cell spreading and metastasis of lung cancer. Cancer Res. 2018;78(20):5927–39.
Google Scholar
Zhou X, Zhou R, Zhou H, Li Q, Hong J, Meng R, et al. ETS-1 induces endothelial-like differentiation and promotes metastasis in non-small cell lung cancer. Cell Physiol Biochem. 2018;45(5):1827–39.
Google Scholar
Li N, Xu L, Zhang J, Liu Y. High level of FHL2 exacerbates the outcome of non-small cell lung cancer (NSCLC) patients and the malignant phenotype in NSCLC cells. Int J Exp Pathol. 2022;103(3):90–101.
Google Scholar
Li M, Zhang J, Meng X, Liu B, Xie SM, Liu F, et al. Limb expression 1-like protein promotes epithelial-mesenchymal transition and epidermal growth factor receptor-tyrosine kinase inhibitor resistance via nucleolin-mediated ribosomal RNA synthesis in non-small cell lung cancer. Cancer Sci. 2023;114(4):1740–56.
Google Scholar
Xu Y, Yang Q, Fang Z, Tan X, Zhang M, Chen W. Trim66 promotes malignant progression of non-small-cell lung cancer cells via targeting MMP9. Comput Math Methods Med. 2022. https://doi.org/10.1155/2022/6058720.
Google Scholar
Yang Y, Li M, Zhou XL, Wang W, Shao Y, Yao JH, et al. Contributes to the maintenance of the cancer stem-like phenotype in non-small cell lung cancer by regulating histone deacetylase 8. Ann Clin Lab Sci. 2022;52(3):439–51.
Google Scholar
Li J, Lu R, Yang K, Sun Q. CircCCT3 enhances invasion and epithelial-mesenchymal transition (EMT) of non-small-cell lung cancer (NSCLC) via the miR-107/Wnt/FGF7 axis. J Oncol. 2022. https://doi.org/10.1155/2022/7020774.
Google Scholar
Meng Q, Liu M, Cheng R. LINC00461/miR-4478/E2F1 feedback loop promotes non-small cell lung cancer cell proliferation and migration. 2020. Biosci Rep. https://doi.org/10.1042/BSR20191345.
Zhang J, Han L, Yu J, Li H, Li QF. miR-224 aggravates cancer-associated fibroblast-induced progression of non-small cell lung cancer by modulating a positive loop of the SIRT3/AMPK/mTOR/HIF-1α axis. Aging-Us. 2021;13(7):10431–49.
Google Scholar
Lu W, Zhang HH, Niu YQ, Wu YF, Sun WJ, Li HY, Kong JL, Ding KF, Shen HM, Wu H et al: Long non-coding RNA linc00673 regulated non-small cell lung cancer proliferation, migration, invasion and epithelial mesenchymal transition by sponging miR-150–5p (vol 16, pg 118, 2017). Mol Cancer. 2017; 16.
Ren WH, Hou JF, Yang CG, Wang HJ, Wu ST, Wu YB, et al. Extracellular vesicles secreted by hypoxia pre-challenged mesenchymal stem cells promote non-small cell lung cancer cell growth and mobility as well as macrophage M2 polarization via miR-21-5p delivery. J Exp Clin Cancer Res. 2019. https://doi.org/10.1186/s13046-019-1027-0.
Google Scholar
Li X, Chen Z, Ni Y, Bian C, Huang J, Chen L, et al. Tumor-associated macrophages secret exosomal miR-155 and miR-196a-5p to promote metastasis of non-small-cell lung cancer. Transl Lung Cancer Res. 2021;10(3):1338–54.
Google Scholar
Li N, Gao WJ, Liu NS. Lncrna BCAR4 promotes proliferation, invasion and metastasis of non-small cell lung cancer cells by affecting epithelial-mesenchymal transition. Eur Rev Med Pharmacol Sci. 2017;21(9):2075–86.
Google Scholar
Yu DJ, Li YH, Zhong M. LncRNA FBXL19-AS1 promotes proliferation and metastasis via regulating epithelial-mesenchymal transition in non-small cell lung cancer. Eur Rev Med Pharmacol Sci. 2019;23(11):4800–6.
Google Scholar
Kreso A, Dick JE. Evolution of the cancer stem cell model. Cell Stem Cell. 2014;14(3):275–91.
Google Scholar
Magee JA, Piskounova E, Morrison SJ. Cancer stem cells: impact, heterogeneity, and uncertainty. Cancer Cell. 2012;21(3):283–96.
Google Scholar
Matchett KB, Lappin TR. Concise reviews: cancer stem cells: from concept to cure. Stem Cells. 2014;32(10):2563–70.
Google Scholar
Sowa T, Menju T, Sonobe M, Nakanishi T, Shikuma K, Imamura N, et al. Association between epithelial-mesenchymal transition and cancer stemness and their effect on the prognosis of lung adenocarcinoma. Cancer Med-Us. 2015;4(12):1853–62.
Google Scholar
Sakurai K, Tomihara K, Furukawa K, Heshiki W, Moniru Z, Noguchi M. Mechanism of autophagy in chemoresistance in oral cancer stem cells. Cancer Sci. 2018;109:1050–1050.
Lorenzo-Sanz L, Muñoz P. Tumor-infiltrating immunosuppressive cells in cancer-cell plasticity, tumor progression and therapy response. Cancer Microenviron. 2019;12(2–3):119–32.
Google Scholar
Maccalli C, Volontè A, Cimminiello C, Parmiani G. Immunology of cancer stem cells in solid tumours. A review. Eur J Cancer. 2014;50(3):649–55.
Google Scholar
Ayob AZ, Ramasamy TS. Cancer stem cells as key drivers of tumour progression. J Biomed Sci. 2018. https://doi.org/10.1186/s12929-018-0426-4.
Google Scholar
Gottschling S, Schnabel PA, Herth FJF, Herpel E. Are we missing the target?–Cancer stem cells and drug resistance in non-small cell lung cancer. Cancer Genomics Proteomics. 2012;9(5):275–86.
Google Scholar
Kim CF, Jackson EL, Woolfenden AE, Lawrence S, Babar I, Vogel S, et al. Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell. 2005;121(6):823–35.
Google Scholar
Fortunato O, Belisario DC, Compagno M, Giovinazzo F, Bracci C, Pastorino U, et al. Cxcr4 inhibition counteracts immunosuppressive properties of metastatic NSCLC stem cells. Front Immunol. 2020. https://doi.org/10.3389/fimmu.2020.02168.
Google Scholar
Jung MJ, Rho JK, Kim YM, Jung JE, Jin YB, Ko YG, et al. Upregulation of CXCR4 is functionally crucial for maintenance of stemness in drug-resistant non-small cell lung cancer cells. Oncogene. 2013;32(2):209–21.
Google Scholar
Horenstein AL, Bracci C, Morandi F, Malavasi F. CD38 in adenosinergic pathways and metabolic re-programming in human multiple myeloma cells: in-tandem insights from basic science to therapy. Front Immunol. 2019;10:760.
Google Scholar
Koren A, Motaln H, Cufer T. Lung cancer stem cells: a biological and clinical perspective. Cell Oncol (Dordr). 2013;36(4):265–75.
Google Scholar
Suresh R, Ali S, Ahmad A, Philip PA, Sarkar FH. 2016 The Role of Cancer Stem Cells in Recurrent and Drug-Resistant Lung Cancer. Lung Cancer Personal Med.. 2016; 890:57-74
Liu J, Xiao Z, Wong SK, Tin VP, Ho KY, Wang J, et al. Lung cancer tumorigenicity and drug resistance are maintained through ALDH(hi)CD44(hi) tumor initiating cells. Oncotarget. 2013;4(10):1698–711.
Google Scholar
Templeton AK, Miyamoto S, Babu A, Munshi A, Ramesh R. Cancer stem cells: progress and challenges in lung cancer. Stem Cell Investig. 2014;1:9.
Google Scholar
Tammela T, Sanchez-Rivera FJ, Cetinbas NM, Wu K, Joshi NS, Helenius K, et al. A Wnt-producing niche drives proliferative potential and progression in lung adenocarcinoma. Nature. 2017;545(7654):355–9.
Google Scholar
Yuan X, Wu H, Han N, Xu H, Chu Q, Yu S, et al. Notch signaling and EMT in non-small cell lung cancer: biological significance and therapeutic application. J Hematol Oncol. 2014;7:87.
Google Scholar
Alamgeer M, Peacock CD, Matsui W, Ganju V, Watkins DN. Cancer stem cells in lung cancer: evidence and controversies. Respirology. 2013;18(5):757–64.
Google Scholar
Garcia Campelo MR, Alonso Curbera G, Aparicio Gallego G, Grande Pulido E, Anton Aparicio LM. Stem cell and lung cancer development: blaming the Wnt, Hh and Notch signalling pathway. Clin Transl Oncol. 2011;13(2):77–83.
Google Scholar
Paul MK, Bisht B, Darmawan DO, Chiou R, Ha VL, Wallace WD, et al. Dynamic changes in intracellular ROS levels regulate airway basal stem cell homeostasis through Nrf2-dependent Notch signaling. Cell Stem Cell. 2014;15(2):199–214.
Google Scholar
Sarode P, Schaefer MB, Grimminger F, Seeger W, Savai R. Macrophage and tumor cell cross-talk is fundamental for lung tumor progression: we need to talk. Front Oncol. 2020;10:324.
Google Scholar
Westhoff B, Colaluca IN, D’Ario G, Donzelli M, Tosoni D, Volorio S, et al. Alterations of the notch pathway in lung cancer. Proc Natl Acad Sci U S A. 2009;106(52):22293–8.
Google Scholar
Levina V, Marrangoni AM, DeMarco R, Gorelik E, Lokshin AE. Drug-selected human lung cancer stem cells: cytokine network, tumorigenic and metastatic properties. PLoS ONE. 2008;3(8):e3077.
Google Scholar
Chang YW, Su YJ, Hsiao M, Wei KC, Lin WH, Liang CL, et al. Diverse targets of β-catenin during the epithelial-mesenchymal transition define cancer stem cells and predict disease relapse. Cancer Res. 2015;75(16):3398–410.
Google Scholar
Zhang Y, Goss AM, Cohen ED, Kadzik R, Lepore JJ, Muthukumaraswamy K, Yang J, DeMayo FJ, AWhitsett J, Parmacek MS, et al. A Gata6-Wnt pathway required for epithelial stem cell development and airway regeneration. Nature Genetics. 2008, 40(7):862–870.
Shi Y, Fu XL, Hua Y, Han Y, Lu Y, Wang JC. The side population in human lung cancer cell line NCI-H460 is enriched in stem-like cancer cells. PLoS ONE. 2012. https://doi.org/10.1371/journal.pone.0033358.
Google Scholar
Tian F, Huberi RM, Schrödl K, Tufman A, Kiefl R, Bergner A: The hedgehog pathway inhibitor GDC-0449 alters intracellular Ca 2+ homeostasis and inhibits cell growth in cisplatin-resistant lung cancer cells. Cancer Res. 2012; 72.
Tiozzo C, De Langhe S, Yu MK, Londhe VA, Carraro G, Li M, et al. Deletion of Pten expands lung epithelial progenitor pools and confers resistance to airway injury. Am J Resp Crit Care. 2009;180(8):701–12.
Google Scholar
Cai S, Li N, Bai X, Liu L, Banerjee A, Lavudi K, et al. ERK inactivation enhances stemness of NSCLC cells via promoting Slug-mediated epithelial-to-mesenchymal transition. Theranostics. 2022;12(16):7051–66.
Google Scholar
Wu Z, He D, Zhao S, Wang H. IL-17A/IL-17RA promotes invasion and activates MMP-2 and MMP-9 expression via p38 MAPK signaling pathway in non-small cell lung cancer. Mol Cell Biochem. 2019;455(1–2):195–206.
Google Scholar
Singh M, Yelle N, Venugopal C, Singh SK. EMT: mechanisms and therapeutic implications. Pharmacol Ther. 2018;182:80–94.
Google Scholar
Battula VL, Evans KW, Hollier BG, Shi Y, Marini FC, Ayyanan A, et al. Epithelial-mesenchymal transition-derived cells exhibit multilineage differentiation potential similar to mesenchymal stem cells. Stem Cells. 2010;28(8):1435–45.
Google Scholar
Du W, Ni L, Liu B, Wei Y, Lv Y, Qiang S, et al. Upregulation of SALL4 by EGFR activation regulates the stemness of CD44-positive lung cancer. Oncogenesis. 2018;7(4):36.
Google Scholar
Leung ELH, Fiscus RR, Tung JW, Tin VPC, Cheng LC, Sihoe ADL, et al. Non-small cell lung cancer cells expressing CD44 are enriched for stem cell-like properties. PLoS ONE. 2010. https://doi.org/10.1371/journal.pone.0014062.
Google Scholar
Zheng Y, Wang LDA, Yin LM, Yao ZR, Tong RZ, Xue JX, et al. Lung cancer stem cell markers as therapeutic targets: an update on signaling pathways and therapies. Front Oncol. 2022. https://doi.org/10.3389/fonc.2022.873994.
Google Scholar
Sakabe T, Azumi J, Haruki T, Umekita Y, Nakamura H, Shiota G. CD117 expression is a predictive marker for poor prognosis in patients with non-small cell lung cancer. Oncol Lett. 2017;13(5):3703–8.
Google Scholar
Levina V, Marrangoni A, Wang TT, Parikh S, Su YY, Herberman R, et al. Elimination of human lung cancer stem cells through targeting of the stem cell factor-c-kit autocrine signaling loop. Cancer Res. 2010;70(1):338–46.
Google Scholar
Eramo A, Lotti F, Sette G, Pilozzi E, Biffoni M, Di Virgilio A, et al. Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death Differ. 2008;15(3):504–14.
Google Scholar
Yamashita N, Oyama T, So T, Yoshimatsu T, Nakano R, Matsunaga W, et al. Association between CD133 expression and prognosis in human lung adenocarcinoma. Cancer Sci. 2022;113:1128–1128.
Prabavathy D, Swarnalatha Y, Ramadoss N. Lung cancer stem cells-origin, characteristics and therapy. Stem Cell Investig. 2018;5:6.
Google Scholar
Zhang WC, Shyh-Chang N, Yang H, Rai A, Umashankar S, Ma S, et al. Glycine decarboxylase activity drives non-small cell lung cancer tumor-initiating cells and tumorigenesis. Cell. 2012;148(1–2):259–72.
Google Scholar
Satar NA, Fakiruddin KS, Lim MN, Mok PL, Zakaria N, Fakharuzi NA, et al. Novel triple-positive markers identified in human non-small cell lung cancer cell line with chemotherapy-resistant and putative cancer stem cell characteristics. Oncol Rep. 2018;40(2):669–81.
Google Scholar
Saintigny P, Burger JA. Recent advances in non-small cell lung cancer biology and clinical management. Discov Med. 2012;13(71):287–97.
Google Scholar
Patel M, Lu L, Zander DS, Sreerama L, Coco D, Moreb JS. ALDH1A1 and ALDH3A1 expression in lung cancers: correlation with histologic type and potential precursors. Lung Cancer. 2008;59(3):340–9.
Google Scholar
Terzuoli E, Bellan C, Aversa S, Ciccone V, Morbidelli L, Giachetti A, et al. ALDH3A1 overexpression in melanoma and lung tumors drives cancer stem cell expansion, impairing immune surveillance through enhanced PD-L1 output. Cancers (Basel). 2019. https://doi.org/10.3390/cancers11121963.
Google Scholar
Xiong D, Ye Y, Fu Y, Wang J, Kuang B, Wang H, et al. Bmi-1 expression modulates non-small cell lung cancer progression. Cancer Biol Ther. 2015;16(5):756–63.
Google Scholar
Zhou N, Wang HJ, Liu HX, Xue HS, Lin F, Meng XT, et al. MTA1-upregulated EpCAM is associated with metastatic behaviors and poor prognosis in lung cancer. J Exp Clin Cancer Res. 2015. https://doi.org/10.1186/s13046-015-0263-1.
Google Scholar
Yang B, Ma YF, Liu Y. Elevated expression of Nrf-2 and ABCG2 involved in multi-drug resistance of lung cancer SP cells. Drug Res (Stuttg). 2015;65(10):526–31.
Google Scholar
Maiuthed A, Chantarawong W, Chanvorachote P. Lung cancer stem cells and cancer stem cell-targeting natural compounds. Anticancer Res. 2018;38(7):3797–809.
Google Scholar
Wang J, Zeng H, Li H, Zhang J, Wang S. Roles of sex-determining region Y-box 2 in cell pluripotency and tumor-related signaling pathways. Mol Clin Oncol. 2015;3(6):1203–7.
Google Scholar
Grimm D, Bauer J, Wise P, Kruger M, Simonsen U, Wehland M, et al. The role of SOX family members in solid tumours and metastasis. Semin Cancer Biol. 2020;67(Pt 1):122–53.
Google Scholar
Wang P, Wan WW, Xiong SL, Feng H, Wu N. Cancer stem-like cells can be induced through dedifferentiation under hypoxic conditions in glioma, hepatoma and lung cancer. Cell Death Discov. 2017. https://doi.org/10.1038/cddiscovery.2016.105.
Google Scholar
Ye T, Li J, Sun Z, Liu Y, Kong L, Zhou S, et al. Nr5a2 promotes cancer stem cell properties and tumorigenesis in nonsmall cell lung cancer by regulating Nanog. Cancer Med. 2019;8(3):1232–45.
Google Scholar
Hombach S, Kretz M. Non-coding RNAs: classification, biology and functioning. Adv Exp Med Biol. 2016;937:3–17.
Google Scholar
Chan JJ, Tay Y. Noncoding RNA:RNA regulatory networks in cancer. Int J Mol Sci. 2018. https://doi.org/10.3390/ijms19051310.
Google Scholar
Guil S, Esteller M. RNA-RNA interactions in gene regulation: the coding and noncoding players. Trends Biochem Sci. 2015;40(5):248–56.
Google Scholar
Anastasiadou E, Jacob LS, Slack FJ. Non-coding RNA networks in cancer. Nat Rev Cancer. 2018;18(1):5–18.
Google Scholar
Ortiz GGR, Mohammadi Y, Nazari A, Ataeinaeini M, Kazemi P, Yasamineh S, et al. A state-of-the-art review on the MicroRNAs roles in hematopoietic stem cell aging and longevity. Cell Commun Signal. 2023;21(1):85.
Google Scholar
Wei K, Ma ZJ, Yang FM, Zhao X, Jiang W, Pan CF, et al. M2 macrophage-derived exosomes promote lung adenocarcinoma progression by delivering miR-942. Cancer Lett. 2022;526:205–16.
Google Scholar
Ma JL, Chen SL, Liu YJ, Han H, Gong M, Song YX. The role of exosomal miR-181b in the crosstalk between NSCLC cells and tumor-associated macrophages. Genes Genomics. 2022;44(10):1243–58.
Google Scholar
Mittal V. Epithelial Mesenchymal Transition in Aggressive Lung Cancers Lung Cancer and Personalized Medicine. Novel Therap Clin Manag. 2016; 890:37- 56
Dong N, Shi L, Wang DC, Chen CS, Wang XD. Role of epigenetics in lung cancer heterogeneity and clinical implication. Semin Cell Dev Biol. 2017;64:18–25.
Google Scholar
Li H, Ouyang RY, Wang Z, Zhou WH, Chen HY, Jiang YW, et al. MiR-150 promotes cellular metastasis in non-small cell lung cancer by targeting FOXO4. Sci Rep. 2016. https://doi.org/10.1038/srep39001.
Google Scholar
Liu Q, Bao HB, Zhang SB, Li CL, Sun GY, Sun XY, et al. Microrna-522-3p promotes brain metastasis in non-small cell lung cancer by targeting Tensin 1 and modulating blood-brain barrier permeability. Exp Cell Res. 2024. https://doi.org/10.1016/j.yexcr.2024.114199.
Google Scholar
Jen J, Tang YA, Lu YH, Lin CC, Lai WW, Wang YC. Oct4 transcriptionally regulates the expression of long non-coding RNAs NEAT1 and MALAT1 to promote lung cancer progression. Mol Cancer. 2017;16(1):104.
Google Scholar
Chen JH, Zhou LY, Xu S, Zheng YL, Wan YF, Hu CP. Overexpression of lncRNA HOXA11-AS promotes cell epithelial-mesenchymal transition by repressing miR-200b in non-small cell lung cancer. Cancer Cell Int. 2017. https://doi.org/10.1186/s12935-017-0433-7.
Google Scholar
Han D, Fang Y, Guo Y, Hong W, Tu J, Wei W. The emerging role of long non-coding RNAs in tumor-associated macrophages. J Cancer. 2019;10(26):6738–46.
Google Scholar
Yin CL, Li J, Li SR, Yang X, Lu YC, Wang CY, et al. LncRNA-HOXC-AS2 regulates tumor-associated macrophage polarization through the STAT1/SOCS1 and STAT1/CIITA pathways to promote the progression of non-small cell lung cancer. Cell Signal. 2024. https://doi.org/10.1016/j.cellsig.2023.111031.
Google Scholar
He Y, Jiang X, Duan L, Xiong Q, Yuan Y, Liu P, et al. LncRNA PKMYT1AR promotes cancer stem cell maintenance in non-small cell lung cancer via activating Wnt signaling pathway. Mol Cancer. 2021;20(1):156.
Google Scholar
Hsu MT, Coca-Prados M. Electron microscopic evidence for the circular form of RNA in the cytoplasm of eukaryotic cells. Nature. 1979;280(5720):339–40.
Google Scholar
Cheng Y, Shi L, Yu YC: Comprehensive analysis of circRNA-miRNA-mRNA in oral squamous cell carcinoma. Arch Oral Biol. 2022; 138.
Wang XT, Li R, Feng LX, Wang J, Qi Q, Wei WJ, et al. Hsa_circ_0001666 promotes non-small cell lung cancer migration and invasion through miR-1184/miR-548I/AGO1 axis. Mol Ther Oncolytics. 2022;24:597–611.
Google Scholar
Ju Y, Yuan B, Wu WA, Zhao J, Shi XR. Circrna ANXA2 promotes lung cancer proliferation and metastasis by upregulating PDPK1 expression. J Oncol. 2021. ;2021(1):4526609. https://doi.org/10.1155/2021/4526609
Gu RH, Shao KF, Xu QX, Zhao X, Qiu HB, Hu HB. Circular RNA hsa_circ_0008003 facilitates tumorigenesis and development of non-small cell lung carcinoma via modulating miR-488/ZNF281 axis. J Cell Mol Med. 2022;26(6):1754–65.
Google Scholar
Zhang N, Nan AR, Chen LJ, Li X, Jia YY, Qiu MY, et al. Circular RNA circSATB2 promotes progression of non-small cell lung cancer cells. Mol Cancer. 2020. https://doi.org/10.1186/s12943-020-01221-6.
Google Scholar
Zhang QJ, Ding F, Zhang CC, Han X, Cheng H. Circ_0001715 functions as a miR-1249-3p sponge to accelerate the progression of non-small cell lung cancer via upregulating the level of FGF5. Biochem Genet. 2023;61(5):1807–26.
Google Scholar
Chen M, Cao C, Ma J. Tumor-related exosomal circ_0001715 promotes lung adenocarcinoma cell proliferation and metastasis via enhancing M2 macrophage polarization by regulating triggering receptor expressed on myeloid cells-2. Thorac Cancer. 2024;15(3):227–38.
Google Scholar
Gao J, Ao YQ, Zhang LX, Deng J, Wang S, Wang HK, et al. Exosomal circZNF451 restrains anti-PD1 treatment in lung adenocarcinoma via polarizing macrophages by complexing with TRIM56 and FXR1. J Exp Clin Cancer Res. 2022;41(1):295.
Google Scholar
Song HM, Meng D, Wang JP, Zhang XY. circRNA hsa_circ_0005909 Predicts Poor Prognosis and Promotes the Growth, Metastasis, and Drug Resistance of Non-Small-Cell Lung Cancer via the miRNA-338-3p/SOX4 Pathway. Dis Markers. 2021;2021:8388512.
Google Scholar
Liao J, Chen Z, Luo X, Su Y, Huang T, Xu H, et al. Hsa_circ_0006692 promotes lung cancer progression via miR-205-5p/CDK19 axis. Genes. 2022. https://doi.org/10.3390/genes13050846.
Google Scholar
Li D, Luo YQ, Gao YW, Yang Y, Wang YN, Xu Y, et al. piR-651 promotes tumor formation in non-small cell lung carcinoma through the upregulation of cyclin D1 and CDK4. Int J Mol Med. 2016;38(3):927–36.
Google Scholar
Pelletier J, Thomas G, Volarevic S. Ribosome biogenesis in cancer: new players and therapeutic avenues (vol 18, pg 51, 2018). Nat Rev Cancer. 2018;18(2):134–134.
Google Scholar
Wang K, Wang S, Zhang Y, Xie L, Song X, Song X. SNORD88C guided 2′-o-methylation of 28S rRNA regulates SCD1 translation to inhibit autophagy and promote growth and metastasis in non-small cell lung cancer. Cell Death Differ. 2023;30(2):341–55.
Google Scholar
Tiong TY, Chan ML, Wang CH, Yadav VK, Pikatan NW, Fong IH, et al. Exosomal miR-21 determines lung-to-brain metastasis specificity through the DGKB/ERK axis within the tumor microenvironment. Life Sci. 2023. https://doi.org/10.1016/j.lfs.2023.121945.
Google Scholar
Chen J, Zhang K, Zhi Y, Wu Y, Chen B, Bai J, et al. Tumor-derived exosomal miR-19b-3p facilitates M2 macrophage polarization and exosomal LINC00273 secretion to promote lung adenocarcinoma metastasis via Hippo pathway. Clin Transl Med. 2021;11(9):e478.
Google Scholar
Fan J. miR-210 transferred by lung cancer cell-derived exosomes may act as proangiogenic factor in cancer-associated fibroblasts by modulating JAK2/STAT3 pathway (vol 134, pg 807, 2020). Clin Sci. 2020;134(13):1801–4.
Google Scholar
Zhang C, Wang H, Liu X, Hu Y, Ding L, Zhang X, et al. Oncogenic microRNA-411 promotes lung carcinogenesis by directly targeting suppressor genes SPRY4 and TXNIP. Oncogene. 2019;38(11):1892–904.
Google Scholar
Liang H, Wang C, Gao K, Li J, Jia R. Muicrorna-421 promotes the progression of non-small cell lung cancer by targeting HOPX and regulating the Wnt/beta-catenin signaling pathway. Mol Med Rep. 2019;20(1):151–61.
Google Scholar
Wang HM, Ma ZL, Liu XM, Zhang CY, Hu YP, Ding L, et al. Mir-183-5p is required for non-small cell lung cancer progression by repressing PTEN. Biomed Pharmacother. 2019;111:1103–11.
Google Scholar
Li Y, Zhang HB, Fan L, Mou JH, Yin Y, Peng C, et al. MiR-629-5p promotes the invasion of lung adenocarcinoma via increasing both tumor cell invasion and endothelial cell permeability. Oncogene. 2020;39(17):3473–88.
Google Scholar
Liang G, Meng W, Huang X, Zhu W, Yin C, Wang C, et al. Mir-196b-5p-mediated downregulation of TSPAN12 and GATA6 promotes tumor progression in non-small cell lung cancer. Proc Natl Acad Sci U S A. 2020;117(8):4347–57.
Google Scholar
Nie J, Yang R, Zhou R, Deng Y, Li DY, Gou DM, et al. Circular RNA circFARSA promotes the tumorigenesis of non-small cell lung cancer by elevating B7H3 via sponging miR-15a-5p. Cell Cycle. 2022;21(24):2575–89.
Google Scholar
Wang Q, Kang PM. Circrna_001010 adsorbs miR-5112 in a sponge form to promote proliferation and metastasis of non-small cell lung cancer (NSCLC). Eur Rev Med Pharmacol Sci. 2020;24(8):4271–80.
Google Scholar
Cui LH, Xu HR, Yang W, Yu LJ. LncRNA PCAT6 promotes non-small cell lung cancer cell proliferation, migration and invasion through regulating miR-330-5p. Onco Targets Ther. 2018;11:7715–24.
Google Scholar
Pan J, Fang S, Tian H, Zhou C, Zhao X, Tian H, et al. lncRNA JPX/miR-33a-5p/Twist1 axis regulates tumorigenesis and metastasis of lung cancer by activating Wnt/beta-catenin signaling. Mol Cancer. 2020;19(1):9.
Google Scholar
Zheng FX, Wang XQ, Zheng WX, Zhao J. Long noncoding RNA HOXA-AS2 promotes cell migration and invasion via upregulating IGF-2 in non-small cell lung cancer as an oncogene. Eur Rev Med Pharmacol Sci. 2019;23(11):4793–9.
Google Scholar
Yu T, Zhao Y, Hu Z, Li J, Chu D, Zhang J, et al. Metalnc9 facilitates lung cancer metastasis via a PGK1-activated AKT/mTOR pathway. Cancer Res. 2017;77(21):5782–94.
Google Scholar
Yao GD, Chen KX, Qin Y, Niu YY, Zhang XF, Xu SD, et al. Long non-coding RNA JHDM1D-AS1 interacts with DHX15 protein to enhance non-small-cell lung cancer growth and metastasis. Mol Ther-Nucl Acids. 2019;18:831–40.
Google Scholar
Jin MZ, Jin WL. The updated landscape of tumor microenvironment and drug repurposing. Signal Transduct Target Ther. 2020;5(1):166.
Google Scholar
Anderson NR, Minutolo NG, Gill S, Klichinsky M. Macrophage-based approaches for cancer immunotherapy. Cancer Res. 2021;81(5):1201–8.
Google Scholar
Hegde S, Leader AM, Merad M. MDSC: markers, development, states, and unaddressed complexity. Immunity. 2021;54(5):875–84.
Google Scholar
de Visser KE, Joyce JA. The evolving tumor microenvironment: from cancer initiation to metastatic outgrowth. Cancer Cell. 2023;41(3):374–403.
Google Scholar
Kargl J, Busch SE, Yang GH, Kim KH, Hanke ML, Metz HE, et al. Neutrophils dominate the immune cell composition in non-small cell lung cancer. Nat Commun. 2017;8:14381.
Google Scholar
Banat GA, Tretyn A, Pullamsetti SS, Wilhelm J, Weigert A, Olesch C, et al. Immune and inflammatory cell composition of human lung cancer stroma. PLoS ONE. 2015;10(9):e0139073.
Google Scholar
Ao YQ, Gao J, Zhang LX, Deng J, Wang S, Lin M, et al. Tumor-infiltrating CD36(+)CD8(+)T cells determine exhausted tumor microenvironment and correlate with inferior response to chemotherapy in non-small cell lung cancer. BMC Cancer. 2023;23(1):367.
Google Scholar
Liu JY, Bai YN, Li YG, Li XL, Luo K. Reprogramming the immunosuppressive tumor microenvironment through nanomedicine: an immunometabolism perspective. EBioMedicine. 2024. https://doi.org/10.1016/j.ebiom.2024.105301.
Google Scholar
Liu S, Chen B, Burugu S, Leung S, Gao D, Virk S, et al. Role of cytotoxic tumor-infiltrating lymphocytes in predicting outcomes in metastatic HER2-positive breast cancer: a secondary analysis of a randomized clinical trial. JAMA Oncol. 2017;3(11):e172085.
Google Scholar
Wu J, Li L, Zhang HB, Zhao YQ, Zhang HH, Wu SY, et al. A risk model developed based on tumor microenvironment predicts overall survival and associates with tumor immunity of patients with lung adenocarcinoma. Oncogene. 2021;40(26):4413–24.
Google Scholar
Shepherd FA, Douillard JY, Blumenschein GR Jr. Immunotherapy for non-small cell lung cancer: novel approaches to improve patient outcome. J Thorac Oncol. 2011;6(10):1763–73.
Google Scholar
Brahmer JR. Harnessing the immune system for the treatment of non-small-cell lung cancer. J Clin Oncol. 2013;31(8):1021–8.
Google Scholar
Forde PM, Reiss KA, Zeidan AM, Brahmer JR. What lies within: novel strategies in immunotherapy for non-small cell lung cancer. Oncologist. 2013;18(11):1203–13.
Google Scholar
Tan ZF, Xue HB, Sun YL, Zhang CAL, Song YL, Qi YF: The Role of Tumor Inflammatory Microenvironment in Lung Cancer. Front Pharmacol. 2021; 12.
Domagala-Kulawik J, Osinska I, Hoser G. Mechanisms of immune response regulation in lung cancer. Transl Lung Cancer Res. 2014;3(1):15–22.
Google Scholar
Ramachandran S, Verma AK, Dev K, Goyal Y, Bhatt D, Alsahli MA, et al. Role of Cytokines and Chemokines in NSCLC Immune Navigation and Proliferation. Oxid Med Cell Longev. 2021;2021:5563746.
Google Scholar
Wang K, Chen X, Lin P, Wu J, Huang Q, Chen ZN, et al. CD147-K148me2-driven tumor cell-macrophage crosstalk provokes NSCLC immunosuppression via the CCL5/CCR5 axis. Adv Sci (Weinh). 2024;11(29):e2400611.
Google Scholar
Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer. 2006;6(5):392–401.
Google Scholar
Ishii G, Ochiai A, Neri S. Phenotypic and functional heterogeneity of cancer-associated fibroblast within the tumor microenvironment. Adv Drug Deliv Rev. 2016;99:186–96.
Google Scholar
Roulis M, Flavell RA. Fibroblasts and myofibroblasts of the intestinal lamina propria in physiology and disease. Differentiation. 2016;92(3):116–31.
Google Scholar
Gaggioli C, Hooper S, Hidalgo-Carcedo C, Grosse R, Marshall JF, Harrington K, et al. Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells. Nat Cell Biol. 2007;9(12):1392–400.
Google Scholar
Calon A, Espinet E, Palomo-Ponce S, Tauriello DV, Iglesias M, Cespedes MV, et al. Dependency of colorectal cancer on a TGF-beta-driven program in stromal cells for metastasis initiation. Cancer Cell. 2012;22(5):571–84.
Google Scholar
O’Connell JT, Sugimoto H, Cooke VG, MacDonald BA, Mehta AI, LeBleu VS, et al. VEGF-A and Tenascin-C produced by S100A4+ stromal cells are important for metastatic colonization. Proc Natl Acad Sci USA. 2011;108(38):16002–7.
Google Scholar
Sahai E, Astsaturov I, Cukierman E, DeNardo DG, Egeblad M, Evans RM, et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat Rev Cancer. 2020;20(3):174–86.
Google Scholar
Fearon DT. The carcinoma-associated fibroblast expressing fibroblast activation protein and escape from immune surveillance. Cancer Immunol Res. 2014;2(3):187–93.
Google Scholar
Mao XQ, Xu J, Wang W, Liang C, Hua J, Liu J, et al. Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives. Mol Cancer. 2021. https://doi.org/10.1186/s12943-021-01428-1.
Google Scholar
Lambrechts D, Wauters E, Boeckx B, Aibar S, Nittner D, Burton O, et al. Phenotype molding of stromal cells in the lung tumor microenvironment. Nat Med. 2018;24(8):1277–89.
Google Scholar
Hanley CJ, Waise S, Ellis MJ, Lopez MA, Pun WY, Taylor J, et al. Single-cell analysis reveals prognostic fibroblast subpopulations linked to molecular and immunological subtypes of lung cancer. Nat Commun. 2023;14(1):387.
Google Scholar
Hao J, Zeltz C, Pintilie M, Li Q, Sakashita S, Wang T, et al. Characterization of distinct populations of carcinoma-associated fibroblasts from non-small cell lung carcinoma reveals a role for ST8SIA2 in cancer cell invasion. Neoplasia. 2019;21(5):482–93.
Google Scholar
Kanaji N, Yokohira M, Nakano-Narusawa Y, Watanabe N, Imaida K, Kadowaki N, Bandoh S: Hepatocyte growth factor produced in lung fibroblasts enhances non-small cell lung cancer cell survival and tumor progression. Respirator Res. 2017; 18.
Navab R, Strumpf D, To C, Pasko E, Kim KS, Park CJ, et al. Integrin α11β1 regulates cancer stromal stiffness and promotes tumorigenicity and metastasis in non-small cell lung cancer. Oncogene. 2016;35(15):1899–908.
Google Scholar
Parajuli H, Teh MT, Abrahamsen S, Christoffersen I, Neppelberg E, Lybak S, et al. Integrin α11 is overexpressed by tumour stroma of head and neck squamous cell carcinoma and correlates positively with alpha smooth muscle actin expression. J Oral Pathol Med. 2017;46(4):267–75.
Google Scholar
Zhu CQ, Popova SN, Brown ER, Barsyte-Lovejoy D, Navab R, Shih W, et al. Integrin alpha 11 regulates IGF2 expression in fibroblasts to enhance tumorigenicity of human non-small-cell lung cancer cells. Proc Natl Acad Sci U S A. 2007;104(28):11754–9. https://doi.org/10.1073/pnas.0703040104
Google Scholar
Li F, Zhao S, Cui Y, Guo T, Qiang J, Xie Q, et al. Α1, 6-fucosyltransferase (FUT8) regulates the cancer-promoting capacity of cancer-associated fibroblasts (CAFs) by modifying EGFR core fucosylation (CF) in non-small cell lung cancer (NSCLC). Am J Cancer Res. 2020;10(3):816.
Google Scholar
Chen MM, Zhang QC, Zheng SJ, Guo XR, Cao LM, Ren YH, et al. Cancer-associated fibroblasts promote migration and invasion of non-small cell lung cancer cells via METTL3-mediated RAC3 m6a modification. Int J Biol Sci. 2023;19(5):1616–32.
Google Scholar
Yang F, Yan YB, Yang Y, Hong X, Wang M, Yang ZY, et al. MiR-210 in exosomes derived from CAFs promotes non-small cell lung cancer migration and invasion through PTEN/PI3K/AKT pathway. Cell Signal. 2020. https://doi.org/10.1016/j.cellsig.2020.109675.
Google Scholar
Ren YH, Cao LM, Wang LM, Zheng SJ, Zhang QC, Guo XR, et al. Autophagic secretion of HMGB1 from cancer-associated fibroblasts promotes metastatic potential of non-small cell lung cancer cells via NFκB signaling. Cell Death Dis. 2021. https://doi.org/10.1038/s41419-021-04150-4.
Google Scholar
Roberts EW, Broz ML, Binnewies M, Headley MB, Nelson AE, Wolf DM, et al. Critical role for CD103(+)/CD141(+) dendritic cells bearing CCR7 for tumor antigen trafficking and priming of T cell immunity in melanoma. Cancer Cell. 2016;30(2):324–36.
Google Scholar
Rizzo M, Alaniz L, Mazzolini GD. Dendritic cell-based therapeutic cancer vaccines. Medicina-B Aires. 2016;76(5):307–14.
Google Scholar
Schneider T, Hoffmann H, Dienemann H, Schnabel PA, Enk AH, Ring S, et al. Non-small cell lung cancer induces an immunosuppressive phenotype of dendritic cells in tumor microenvironment by upregulating B7–H3. J Thorac Oncol. 2011;6(7):1162–8.
Google Scholar
Sun Y, Wang Y, Zhao J, Gu M, Giscombe R, Lefvert AK, et al. B7–H3 and B7–H4 expression in non-small-cell lung cancer. Lung Cancer. 2006;53(2):143–51.
Google Scholar
Zhang RF, Shao FC, Wu XH, Ying KJ. Value of quantitative analysis of circulating cell free DNA as a screening tool for lung cancer: a meta-analysis. Lung Cancer. 2010;69(2):225–31.
Google Scholar
Masten BJ, Olson GK, Tarleton CA, Rund C, Schuyler M, Mehran R, et al. Characterization of myeloid and plasmacytoid dendritic cells in human lung. J Immunol. 2006;177(11):7784–93.
Google Scholar
Shi WW, Li XY, Porter JL, Ostrodi DH, Yang B, Li J, et al. Level of plasmacytoid dendritic cells is increased in non-small cell lung carcinoma. Tumor Biol. 2014;35(3):2247–52.
Google Scholar
Sorrentino R, Terlizzi M, Di Crescenzo VG, Popolo A, Pecoraro M, Perillo G, et al. Human lung cancer-derived immunosuppressive plasmacytoid dendritic cells release IL-1alpha in an AIM2 inflammasome-dependent manner. Am J Pathol. 2015;185(11):3115–24.
Google Scholar
Yang Z, Guo J, Weng L, Tang W, Jin S, Ma W. Myeloid-derived suppressor cells-new and exciting players in lung cancer. J Hematol Oncol. 2020;13(1):10.
Google Scholar
Cheng JN, Yuan YX, Zhu B, Jia Q. Myeloid-derived suppressor cells: a multifaceted accomplice in tumor progression. Front Cell Dev Biol. 2021;9:740827.
Google Scholar
Tcyganov E, Mastio J, Chen E, Gabrilovich DI. Plasticity of myeloid-derived suppressor cells in cancer. Curr Opin Immunol. 2018;51:76–82.
Google Scholar
Bronte V, Brandau S, Chen SH, Colombo MP, Frey AB, Greten TF, et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun. 2016. https://doi.org/10.1038/ncomms12150.
Google Scholar
Chen Z, Yuan R, Hu S, Yuan W, Sun Z. Roles of the exosomes derived from myeloid-derived suppressor cells in tumor immunity and cancer progression. Front Immunol. 2022;13:817942.
Google Scholar
Damuzzo V, Pinton L, Desantis G, Solito S, Marigo I, Bronte V, et al. Complexity and challenges in defining myeloid-derived suppressor cells. Cytometry Part B Clinical Cytometry. 2015;88(2):77–91.
Google Scholar
Yamauchi Y, Safi S, Blattner C, Rathinasamy A, Umansky L, Juenger S, et al. Circulating and tumor myeloid-derived suppressor cells in resectable non-small cell lung cancer. Am J Respir Crit Care Med. 2018;198(6):777–87.
Google Scholar
He ZN, Zhang CY, Zhao YW, He SL, Li Y, Shi BL, et al. Regulation of T cells by myeloid-derived suppressor cells: emerging immunosuppressor in lung cancer. Discov Oncol. 2023;14(1):185.
Google Scholar
Liu CY, Wang YM, Wang CL, Feng PH, Ko HW, Liu YH, et al. Population alterations of L-arginase- and inducible nitric oxide synthase-expressed CD11b+/CD14(-)/CD15+/CD33+ myeloid-derived suppressor cells and CD8+ T lymphocytes in patients with advanced-stage non-small cell lung cancer. J Cancer Res Clin Oncol. 2010;136(1):35–45.
Google Scholar
Feng PH, Lee KY, Chang YL, Kuo HP. CD14+S100A9 high monocytic myeloid-derived suppressor cells and their clinical relevance in non-small cell lung cancer. Cancer Res. 2012; 72.
Allard B, Longhi MS, Robson SC, Stagg J. The ectonucleotidases CD39 and CD73: novel checkpoint inhibitor targets. Immunol Rev. 2017;276(1):121–44.
Google Scholar
Li J, Wang L, Chen X, Li L, Li Y, Ping Y, et al. CD39/CD73 upregulation on myeloid-derived suppressor cells via TGF-beta-mTOR-HIF-1 signaling in patients with non-small cell lung cancer. Oncoimmunology. 2017;6(6):e1320011.
Google Scholar
Burke MC, Oei MS, Edwards NJ, Ostrand-Rosenberg S, Fenselau C. Ubiquitinated proteins in exosomes secreted by myeloid-derived suppressor cells. J Proteome Res. 2014;13(12):5965–72. https://doi.org/10.1021/pr500854x
Google Scholar
Zhang XJ, Li F, Tang Y, Ren QL, Xiao B, Wan Y, et al. Mir-21a in exosomes from Lewis lung carcinoma cells accelerates tumor growth through targeting PDCD4 to enhance expansion of myeloid-derived suppressor cells. Oncogene. 2020;39(40):6354–69.
Google Scholar
Orooji N, Fadaee M, Kazemi T, Yousefi B. Exosome therapeutics for non-small cell lung cancer tumorigenesis. Cancer Cell Int. 2024;24(1):360.
Google Scholar
Fu XG, Deng J, Xu WJ, Chen JY, Sun J, Deng H. Histidine decarboxylase-expressing PMN-MDSC-derived TGF-β1 promotes the epithelial-mesenchymal transition of metastatic lung adenocarcinoma. Int J Clin Exp Pathol. 2020;13(6):1361–71.
Google Scholar
Li YD, Lamano JB, Lamano JB, Quaggin-Smith J, Veliceasa D, Kaur G, et al. Tumor-induced peripheral immunosuppression promotes brain metastasis in patients with non-small cell lung cancer. Cancer Immunol Immunother. 2019;68(9):1501–13.
Google Scholar
Lin S, Zhang X, Huang G, Cheng L, Lv J, Zheng D, et al. Myeloid-derived suppressor cells promote lung cancer metastasis by CCL11 to activate ERK and AKT signaling and induce epithelial-mesenchymal transition in tumor cells. Oncogene. 2021;40(8):1476–89.
Google Scholar
Dudás J, Ladányi A, Ingruber J, Steinbichler TB, Riechelmann H. Epithelial to mesenchymal transition: a mechanism that fuels cancer radio/chemoresistance. Cells. 2020. https://doi.org/10.3390/cells9020428.
Google Scholar
Chae YK, Chang SM, Ko T, Anker J, Agte S, Iams W, et al. Epithelial-mesenchymal transition (EMT) signature is inversely associated with T-cell infiltration in non-small cell lung cancer (NSCLC). Sci Rep. 2018. https://doi.org/10.1038/s41598-018-21061-1.
Google Scholar
Kloosterman DJ, Akkari L. Macrophages at the interface of the co-evolving cancer ecosystem. Cell. 2023;186(8):1627–51.
Google Scholar
Kzhyshkowska J, Shen JX, Larionova I. Targeting of TAMs: can we be more clever than cancer cells? Cell Mol Immunol. 2024;21(12):1376–409.
Google Scholar
Redente EF, Dwyer-Nield LD, Merrick DT, Raina K, Agarwal R, Pao W, et al. Tumor progression stage and anatomical site regulate tumor-associated macrophage and bone marrow-derived monocyte polarization. Am J Pathol. 2010;176(6):2972–85.
Google Scholar
Wang F, Yang M, Luo W, Zhou Q. Characteristics of tumor microenvironment and novel immunotherapeutic strategies for non-small cell lung cancer. J Natl Cancer Cent. 2022;2(4):243–62.
Google Scholar
Larionova I, Tuguzbaeva G, Ponomaryova A, Stakheyeva M, Cherdyntseva N, Pavlov V, et al. Tumor-associated macrophages in human breast, colorectal, lung, ovarian and prostate cancers. Front Oncol. 2020;10:566511.
Google Scholar
Wang R, Lu M, Zhang J, Chen S, Luo X, Qin Y, et al. Increased IL-10 mRNA expression in tumor-associated macrophage correlated with late stage of lung cancer. J Exp Clin Cancer Res. 2011;30(1):62.
Google Scholar
Zeni E, Mazzetti L, Miotto D, Lo Cascio N, Maestrelli P, Querzoli P, et al. Macrophage expression of interleukin-10 is a prognostic factor in nonsmall cell lung cancer. Eur Respir J. 2007;30(4):627–32.
Google Scholar
Liang ZW, Ge XX, Xu MD, Qin HL, Wu MY, Shen M, et al. Tumor-associated macrophages promote the metastasis and growth of non-small-cell lung cancer cells through NF-κB/PP2Ac-positive feedback loop. Cancer Sci. 2021;112(6):2140–57.
Google Scholar
Wu J, Gao W, Tang Q, Yu Y, You W, Wu Z, et al. M2 macrophage-derived exosomes facilitate HCC metastasis by transferring alpha(M) beta(2) integrin to tumor cells. Hepatology. 2021;73(4):1365–80.
Google Scholar
Yang C, Dou R, Wei C, Liu K, Shi D, Zhang C, et al. Tumor-derived exosomal microRNA-106b-5p activates EMT-cancer cell and M2-subtype TAM interaction to facilitate CRC metastasis. Mol Ther. 2021;29(6):2088–107.
Google Scholar
Yang L, Dong Y, Li Y, Wang D, Liu S, Wang D, et al. IL-10 derived from M2 macrophage promotes cancer stemness via JAK1/STAT1/NF-kappaB/Notch1 pathway in non-small cell lung cancer. Int J Cancer. 2019;145(4):1099–110.
Google Scholar
Matanic D, Beg-Zec Z, Stojanovic D, Matakoric N, Flego V, Milevoj-Ribic F. Cytokines in patients with lung cancer. Scand J Immunol. 2003;57(2):173–8.
Google Scholar
Pine SR, Mechanic LE, Enewold L, Chaturvedi AK, Katki HA, Zheng YL, et al. Increased levels of circulating interleukin 6, interleukin 8, C-reactive protein, and risk of lung cancer. J Natl Cancer Inst. 2011;103(14):1112–22.
Google Scholar
Song XY, Zhou SJ, Xiao N, Li YS, Zhen DZ, Su CY, et al. Research on the relationship between serum levels of inflammatory cytokines and non-small cell lung cancer. Asian Pac J Cancer Prev. 2013;14(8):4765–8.
Google Scholar
Vahl JM, Friedrich J, Mittler S, Trump S, Heim L, Kachler K, et al. Interleukin-10-regulated tumour tolerance in non-small cell lung cancer. Br J Cancer. 2017;117(11):1644–55.
Google Scholar
La Fleur L, Botling J, He F, Pelicano C, Zhou C, He C, et al. Targeting MARCO and IL37R on immunosuppressive macrophages in lung cancer blocks regulatory T cells and supports cytotoxic lymphocyte function. Cancer Res. 2021;81(4):956–67.
Google Scholar
Zhao L, Zhang H, Liu X, Xue S, Chen D, Zou J, et al. TGR5 deficiency activates antitumor immunity in non-small cell lung cancer via restraining M2 macrophage polarization. Acta Pharm Sin B. 2022;12(2):787–800.
Google Scholar
Bharadwaj S, Groza Y, Mierzwicka JM, Maly P. Current understanding on TREM-2 molecular biology and physiopathological functions. Int Immunopharmacol. 2024;134:112042.
Google Scholar
Zhang H, Liu Z, Wen H, Guo Y, Xu F, Zhu Q, et al. Immunosuppressive TREM2(+) macrophages are associated with undesirable prognosis and responses to anti-PD-1 immunotherapy in non-small cell lung cancer. Cancer Immunol Immunother. 2022;71(10):2511–22.
Google Scholar
Wu LG, Cheng DA, Yang X, Zhao WQ, Fang C, Chen R, Ji M: M2-TAMs promote immunoresistance in lung adenocarcinoma by enhancing-mediated m6A methylation. Annal Transl Med. 2022; 10(24).
Wettersten HI, Weis SM, Pathria P, Von Schalscha T, Minami T, Varner JA, et al. Arming tumor-associated macrophages to reverse epithelial cancer progression. Cancer Res. 2019;79(19):5048–59.
Google Scholar
Baghdadi M, Wada H, Nakanishi S, Abe H, Han N, Putra WE, et al. Chemotherapy-induced IL34 enhances immunosuppression by tumor-associated macrophages and mediates survival of chemoresistant lung cancer cells. Cancer Res. 2016;76(20):6030–42.
Google Scholar
Whiteside TL. FOXP3+ treg as a therapeutic target for promoting anti-tumor immunity. Expert Opin Ther Targets. 2018;22(4):353–63. https://doi.org/10.1080/14728222.2018.1451514
Google Scholar
La Cava A. Natural Tregs and autoimmunity. Front Biosci. 2009;14(1):333–43.
Google Scholar
Togashi Y, Nishikawa H. Regulatory t cells: molecular and cellular basis for immunoregulation. Curr Top Microbiol Immunol. 2017;410:3–27.
Google Scholar
Sakaguchi S, Miyara M, Costantino CM, Hafler DA. FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol. 2010;10(7):490–500.
Google Scholar
He J, Hu Y, Hu M, Li B. Development of PD-1/PD-L1 pathway in tumor immune microenvironment and treatment for non-small cell lung cancer. Sci Rep. 2015;5:13110.
Google Scholar
Ohue Y, Nishikawa H. Regulatory T (Treg) cells in cancer: can Treg cells be a new therapeutic target? Cancer Sci. 2019;110(7):2080–9.
Google Scholar
Togashi Y, Shitara K, Nishikawa H. Regulatory T cells in cancer immunosuppression—implications for anticancer therapy. Nat Rev Clin Oncol. 2019;16(6):356–71.
Google Scholar
Mierzwicka JM, Petrokova H, Kafkova LR, Kosztyu P, Cerny J, Kuchar M, et al. Engineering PD-1-targeted small protein variants for in vitro diagnostics and in vivo PET imaging. J Transl Med. 2024;22(1):426.
Google Scholar
Ganesan AP, Johansson M, Ruffell B, Yagui-Beltran A, Lau J, Jablons DM, et al. Tumor-infiltrating regulatory T cells inhibit endogenous cytotoxic T cell responses to lung adenocarcinoma. J Immunol. 2013;191(4):2009–17.
Google Scholar
Domvri K, Petanidis S, Zarogoulidis P, Anestakis D, Tsavlis D, Bai C, et al. Treg-dependent immunosuppression triggers effector T cell dysfunction via the STING/ILC2 axis. Clin Immunol. 2021;222:108620.
Google Scholar
Shimizu K, Nakata M, Hirami Y, Yukawa T, Maeda A, Tanemoto K. Tumor-infiltrating Foxp3+ regulatory T cells are correlated with cyclooxygenase-2 expression and are associated with recurrence in resected non-small cell lung cancer. J Thorac Oncol. 2010;5(5):585–90.
Google Scholar
Razani-Boroujerdi S, Sopori ML. Early manifestations of NNK-induced lung cancer: role of lung immunity in tumor susceptibility. Am J Respir Cell Mol Biol. 2007;36(1):13–9.
Google Scholar
Smyth MJ, Teng MW, Swann J, Kyparissoudis K, Godfrey DI, Hayakawa Y. CD4+CD25+ T regulatory cells suppress NK cell-mediated immunotherapy of cancer. J Immunol. 2006;176(3):1582–7.
Google Scholar
Erfani N, Mehrabadi SM, Ghayumi MA, Haghshenas MR, Mojtahedi Z, Ghaderi A, et al. Increase of regulatory T cells in metastatic stage and CTLA-4 over expression in lymphocytes of patients with non-small cell lung cancer (NSCLC). Lung Cancer. 2012;77(2):306–11.
Google Scholar
Petersen RP, Campa MJ, Sperlazza J, Conlon D, Joshi MB, Harpole DH Jr., et al. Tumor infiltrating Foxp3+ regulatory T-cells are associated with recurrence in pathologic stage I NSCLC patients. Cancer. 2006;107(12):2866–72.
Google Scholar
Schneider T, Kimpfler S, Warth A, Schnabel PA, Dienemann H, Schadendorf D, et al. Foxp3(+) regulatory T cells and natural killer cells distinctly infiltrate primary tumors and draining lymph nodes in pulmonary adenocarcinoma. J Thorac Oncol. 2011;6(3):432–8.
Google Scholar
Black CC, Turk MJ, Dragnev K, Rigas JR. Adenocarcinoma contains more immune tolerance regulatory T-cell lymphocytes (versus squamous carcinoma) in non-small-cell lung cancer. Lung. 2013;191(3):265–70.
Google Scholar
Domagala-Kulawik J, Hoser G, Safianowska A, Grubek-Jaworska H, Chazan R. Elevated TGF-beta1 concentration in bronchoalveolar lavage fluid from patients with primary lung cancer. Arch Immunol Ther Exp (Warsz). 2006;54(2):143–7.
Google Scholar
Ni XY, Sui HX, Liu Y, Ke SZ, Wang YN, Gao FG. TGF-β of lung cancer microenvironment upregulates B7H1 and GITRL expression in dendritic cells and is associated with regulatory T cell generation. Oncol Rep. 2012;28(2):615–21.
Google Scholar
Yan F, Du RJ, Wei F, Zhao H, Yu JP, Wang CL, et al. Expression of TNFR2 by regulatory T cells in peripheral blood is correlated with clinical pathology of lung cancer patients. Cancer Immunol Immunother. 2015;64(11):1475–85.
Google Scholar
Ye LL, Peng WB, Niu YR, Xiang X, Wei XS, Wang ZH, et al. Accumulation of TNFR2-expressing regulatory T cells in malignant pleural effusion of lung cancer patients is associated with poor prognosis. Ann Transl Med. 2020. https://doi.org/10.21037/atm-20-7181.
Google Scholar
Woo EY, Chu CS, Goletz TJ, Schlienger K, Yeh H, Coukos G, et al. Regulatory CD4(+)CD25(+) T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer. Cancer Res. 2001;61(12):4766–72.
Google Scholar
Woo EY, Yeh H, Chu CS, Schlienger K, Carroll RG, Riley JL, et al. Cutting edge: Regulatory T cells from lung cancer patients directly inhibit autologous T cell proliferation. J Immunol. 2002;168(9):4272–6.
Google Scholar
Gaffen SL, Jain R, Garg AV, Cua DJ. The IL-23-IL-17 immune axis: from mechanisms to therapeutic testing. Nat Rev Immunol. 2014;14(9):585–600.
Google Scholar
Ye J, Livergood RS, Peng G. The role and regulation of human Th17 cells in tumor immunity. Am J Pathol. 2013;182(1):10–20.
Google Scholar
Aggarwal S, Gurney AL. IL-17: prototype member of an emerging cytokine family. J Leukoc Biol. 2002;71(1):1–8.
Google Scholar
Lücke J, Shiri AM, Zhang T, Kempski J, Giannou AD, Huber S. Rationalizing heptadecaphobia: TH17 cells and associated cytokines in cancer and metastasis. FEBS J. 2021;288(24):6942–71.
Google Scholar
Pan B, Shen J, Cao JY, Zhou YX, Shang LH, Jin S, Cao SB, Che DH, Liu F, Yu Y: Interleukin-17 promotes angiogenesis by stimulating VEGF production of cancer cells via the STAT3/GIV signaling pathway in non-small-cell lung cancer (vol 5, 16053, 2015). Sci Rep-Uk 2020; 10(1).
Cortez-Retamozo V, Etzrodt M, Newton A, Rauch PJ, Chudnovskiy A, Berger C, et al. Origins of tumor-associated macrophages and neutrophils. P Natl Acad Sci USA. 2012;109(7):2491–6.
Google Scholar
Andzinski L, Kasnitz N, Stahnke S, Wu CF, Gereke M, von Kockritz-Blickwede M, et al. Type I IFNs induce anti-tumor polarization of tumor associated neutrophils in mice and human. Int J Cancer. 2016;138(8):1982–93.
Google Scholar
Sionov RV, Fridlender ZG, Granot Z. The multifaceted roles neutrophils play in the tumor microenvironment. Cancer Microenviron. 2015;8(3):125–58. https://doi.org/10.1007/s12307-014-0147-5
Google Scholar
Hedrick CC, Malanchi I. Neutrophils in cancer: heterogeneous and multifaceted. Nat Rev Immunol. 2022;22(3):173–87.
Google Scholar
Houghton AM, Rzymkiewicz DM, Ji H, Gregory AD, Egea EE, Metz HE, et al. Neutrophil elastase-mediated degradation of IRS-1 accelerates lung tumor growth. Nat Med. 2010;16(2):219–23.
Google Scholar
Wislez M, Antoine M, Rabbe N, Gounant V, Poulot V, Lavole A, et al. Neutrophils promote aerogenous spread of lung adenocarcinoma with bronchioloalveolar carcinoma features. Clin Cancer Res. 2007;13(12):3518–27.
Google Scholar
Zhou J, Jiang S, Wang W, Liu R. Research Progress of Tumor-Associated Neutrophils and Lung Cancer. Zhongguo Fei Ai Za Zhi. 2019;22(11):727–31.
Google Scholar
Hu P, Shen M, Zhang P, Zheng C, Pang Z, Zhu L, et al. Intratumoral neutrophil granulocytes contribute to epithelial-mesenchymal transition in lung adenocarcinoma cells. Tumour Biol. 2015;36(10):7789–96.
Google Scholar
Mayer C, Darb-Esfahani S, Meyer AS, Hubner K, Rom J, Sohn C, et al. Neutrophil granulocytes in ovarian cancer – induction of epithelial-to-mesenchymal-transition and tumor cell migration. J Cancer. 2016;7(5):546–54.
Google Scholar
Faget J, Groeneveld S, Boivin G, Sankar M, Zangger N, Garcia M, et al. Neutrophils and snail orchestrate the establishment of a pro-tumor microenvironment in lung cancer. Cell Rep. 2017;21(11):3190–204.
Google Scholar
Michaeli J, Shaul ME, Mishalian I, Hovav AH, Levy L, Zolotriov L, et al. Tumor-associated neutrophils induce apoptosis of non-activated CD8 T-cells in a TNFalpha and NO-dependent mechanism, promoting a tumor-supportive environment. Oncoimmunology. 2017;6(11):e1356965.
Google Scholar
Enfield KSS, Colliver E, Lee C, Magness A, Moore DA, Sivakumar M, et al. Spatial architecture of myeloid and T cells orchestrates immune evasion and clinical outcome in lung cancer. Cancer Discov. 2024;14(6):1018–47.
Google Scholar
Gillies RJ, Kinahan PE, Hricak H. Radiomics: images are more than pictures, they are data. Radiology. 2016;278(2):563–77.
Google Scholar
Tang WF, Wu M, Bao H, Xu Y, Lin JS, Liang Y, et al. Timing and origins of local and distant metastases in lung cancer. J Thorac Oncol. 2021;16(7):1136–48.
Google Scholar
Song KJ, Choi S, Kim K, Hwang HS, Chang E, Park JS, et al. Proteogenomic analysis reveals non-small cell lung cancer subtypes predicting chromosome instability, and tumor microenvironment. Nat Commun. 2024;15(1):10164.
Google Scholar
Zhu EJ, Muneer A, Zhang JJ, Xia Y, Li XM, Zhou CC, et al. Progress and challenges of artificial intelligence in lung cancer clinical translation. NPJ Precis Oncol. 2025. https://doi.org/10.1038/s41698-025-00986-7.
Google Scholar
Mei T, Wang T, Zhou Q. Multi-omics and artificial intelligence predict clinical outcomes of immunotherapy in non-small cell lung cancer patients. Clin Exp Med. 2024;24(1):60.
Google Scholar
Chen L, Chen B, Zhao Z, Shen L. Using artificial intelligence based imaging to predict lymph node metastasis in non-small cell lung cancer: a systematic review and meta-analysis. Quant Imaging Med Surg. 2024;14(10):7496–512.
Google Scholar
Barrera C, Corredor G, Viswanathan VS, Ding RW, Toro P, Fu PF, et al. Deep computational image analysis of immune cell niches reveals treatment-specific outcome associations in lung cancer. NPJ Precis Oncol. 2023. https://doi.org/10.1038/s41698-023-00403-x.
Google Scholar
Wang S, Rong R, Yang DM, Fujimoto J, Yan S, Cai L, et al. Computational staining of pathology images to study the tumor microenvironment in lung cancer. Cancer Res. 2020;80(10):2056–66.
Google Scholar
Bębas E, Borowska M, Derlatka M, Oczeretko E, Hładuński M, Szumowski P, et al. Machine-learning-based classification of the histological subtype of non-small-cell lung cancer using MRI texture analysis. Biomed Signal Process Control. 2021;66:102446.
Google Scholar
Coudray N, Ocampo PS, Sakellaropoulos T, Narula N, Snuderl M, Fenyo D, et al. Classification and mutation prediction from non-small cell lung cancer histopathology images using deep learning. Nat Med. 2018;24(10):1559–67.
Google Scholar
Liu H, Jing B, Han W, Long Z, Mo X, Li H. A comparative texture analysis based on NECT and CECT images to differentiate lung adenocarcinoma from squamous cell carcinoma. J Med Syst. 2019;43(3):59.
Google Scholar
Shen H, Chen L, Liu K, Zhao K, Li J, Yu L, et al. A subregion-based positron emission tomography/computed tomography (PET/CT) radiomics model for the classification of non-small cell lung cancer histopathological subtypes. Quant Imaging Med Surg. 2021;11(7):2918–32.
Google Scholar
Ma Y, Feng W, Wu ZY, Liu MY, Zhang F, Liang ZG, et al. Intra-tumoural heterogeneity characterization through texture and colour analysis for differentiation of non-small cell lung carcinoma subtypes. Phys Med Biol. 2018. https://doi.org/10.1088/1361-6560/aad648.
Google Scholar
Zhou Z, Wang M, Zhao R, Shao Y, Xing L, Qiu Q, et al. A multi-task deep learning model for EGFR genotyping prediction and GTV segmentation of brain metastasis. J Transl Med. 2023;21(1):788.
Google Scholar
Wang S, Shi J, Ye Z, Dong D, Yu D, Zhou M, et al. Predicting EGFR mutation status in lung adenocarcinoma on computed tomography image using deep learning. Eur Respir J. 2019. https://doi.org/10.1183/13993003.00986-2018.
Google Scholar
Li Y, Lv XN, Wang B, Xu ZX, Wang YC, Gao S, et al. Differentiating EGFR from ALK mutation status using radiomics signature based on MR sequences of brain metastasis. Eur J Radiol. 2022. https://doi.org/10.1016/j.ejrad.2022.110499.
Google Scholar
He X, Guan C, Chen T, Wu H, Su L, Zhao M, et al. Predicting brain metastases in EGFR-positive lung adenocarcinoma patients using pre-treatment CT lung imaging data. Eur J Radiol. 2025;190:112265.
Google Scholar
Duan FR, Zhang MH, Yang CY, Wang XW, Wang DL. Non-invasive prediction of lymph node metastasis in NSCLC using clinical, radiomics, and deep learning features from 18F-FDG PET/CT based on interpretable machine learning. Acad Radiol. 2025;32(3):1645–55.
Google Scholar
Zhao Y, Xiong S, Ren Q, Wang J, Li M, Yang L, et al. Deep learning using histological images for gene mutation prediction in lung cancer: a multicentre retrospective study. Lancet Oncol. 2025;26(1):136–46.
Google Scholar
Patkar S, Chen A, Basnet A, Bixby A, Rajendran R, Chernet R, et al. Author correction: predicting the tumor microenvironment composition and immunotherapy response in non-small cell lung cancer from digital histopathology images. NPJ Precis Oncol. 2025;9(1):6.
Google Scholar
Harms PW, Frankel TL, Moutafi M, Rao A, Rimm DL, Taube JM, et al. Multiplex immunohistochemistry and immunofluorescence: a practical update for pathologists. Mod Pathol. 2023;36(7):100197.
Google Scholar
Chen P, Zhang J, Wu J. Artificial intelligence in digital pathology to advance cancer immunotherapy. 21st century pathology. 2022;2(3):120.
Google Scholar
Wang X, Bera K, Barrera C, Zhou Y, Lu C, Vaidya P, et al. A prognostic and predictive computational pathology image signature for added benefit of adjuvant chemotherapy in early stage non-small-cell lung cancer. EBioMedicine. 2021;69:103481.
Google Scholar
Šarić M, Russo M, Stella M, Sikora M: CNN-based method for lung cancer detection in whole slide histopathology images. In: 2019: IEEE: 1–4. https://doi.org/10.1109/ICTEST64710.2025.11042717
Jeong DY, Park J, Song H, Moon J, Lee T, Ahn C, et al. Abstract 4170: Artificial intelligence (AI)-based multi-modal approach using H&E and CT image for predicting treatment response of immune checkpoint inhibitor (ICI) in non-small cell lung cancer (NSCLC). Cancer Res. 2024;84(6_Supplement):4170–4170.
Google Scholar
Kim L, Shin S, Cho SI, Jung W, Song S, Chung LIY, et al. Artificial intelligence (AI)-powered H&E whole-slide image (WSI) analysis of tertiary lymphoid structure (TLS) to predict response to immunotherapy in non-small cell lung cancer (NSCLC). J Clin Oncol. 2024. https://doi.org/10.1200/JCO.2024.42.16_suppl.3135.
Google Scholar
Gandhi Z, Gurram P, Amgai B, Lekkala SP, Lokhandwala A, Manne S, et al. Artificial intelligence and lung cancer: impact on improving patient outcomes. Cancers (Basel). 2023. https://doi.org/10.3390/cancers15215236.
Google Scholar
Bardoni C, Spaggiari L, Bertolaccini L. Artificial intelligence in lung cancer. Ann Transl Med. 2024;12(4):79.
Google Scholar
Lei F. The application of artificial intelligence in lung cancer research. Cancer Control. 2024;31:10732748241297373.
Google Scholar
Yang D, Miao Y, Liu C, Zhang N, Zhang D, Guo Q, et al. Advances in artificial intelligence applications in the field of lung cancer. Front Oncol. 2024;14:1449068.
Google Scholar
Wang Y, Zhang W, Liu X, Tian L, Li W, He P, et al. Artificial intelligence in precision medicine for lung cancer: a bibliometric analysis. Digit Health. 2025;11:20552076241300229.
Google Scholar
Binnewies M, Roberts EW, Kersten K, Chan V, Fearon DF, Merad M, et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med. 2018;24(5):541–50.
Google Scholar
Tsui DCC, Camidge DR, Rusthoven CG. Managing central nervous system spread of lung cancer: the state of the art. J Clin Oncol. 2022;40(6):642–60.
Google Scholar
Wilkerson MD, Yin X, Walter V, Zhao N, Cabanski CR, Hayward MC, et al. Differential pathogenesis of lung adenocarcinoma subtypes involving sequence mutations, copy number, chromosomal instability, and methylation. PLoS ONE. 2012;7(5):e36530.
Google Scholar
Bos PD, Zhang XHF, Nadal C, Shu WP, Gomis RR, Nguyen DX, et al. Genes that mediate breast cancer metastasis to the brain. Nature. 2009;459(7249):1005-U1137.
Google Scholar
Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell. 2004;117(7):927–39.
Google Scholar
Cook LM, Hurst DR, Welch DR. Metastasis suppressors and the tumor microenvironment. Semin Cancer Biol. 2011;21(2):113–22.
Google Scholar
Steeg PS, Bevilacqua G, Kopper L, Thorgeirsson UP, Talmadge JE, Liotta LA, et al. Evidence for a novel gene associated with low tumor metastatic potential. J Natl Cancer Inst. 1988;80(3):200–4.
Google Scholar
Ji H, Ramsey MR, Hayes DN, Fan C, McNamara K, Kozlowski P, et al. LKB1 modulates lung cancer differentiation and metastasis. Nature. 2007;448(7155):807–10.
Google Scholar
Carretero J, Shimamura T, Rikova K, Jackson AL, Wilkerson MD, Borgman CL, et al. Integrative genomic and proteomic analyses identify targets for Lkb1-deficient metastatic lung tumors. Cancer Cell. 2010;17(6):547–59.
Google Scholar
Yu KH, Snyder M. Omics profiling in precision oncology. Mol Cell Proteomics. 2016;15(8):2525–36.
Google Scholar
Yu KH, Wang F, Berry GJ, Re C, Altman RB, Snyder M, et al. Classifying non-small cell lung cancer types and transcriptomic subtypes using convolutional neural networks. J Am Med Inform Assoc. 2020;27(5):757–69.
Google Scholar
Cheng N, Liu J, Chen C, Zheng T, Li C, Huang J. Prediction of lung cancer metastasis by gene expression. Comput Biol Med. 2023;153:106490.
Google Scholar
Wang XL, Zhou Y, Lu XM, Shao LL. Machine learning models reveal ARHGAP11A’s impact on lymph node metastasis and stemness in NSCLC. BioFactors. 2025. https://doi.org/10.1002/biof.2141.
Google Scholar
Zhang K, Yang X, Wang YF, Yu YF, Huang N, Li G, et al. Artificial intelligence in drug development. Nat Med. 2025;31(1):45–59.
Google Scholar
Zhu E, Muneer A, Zhang J, Xia Y, Li X, Zhou C, et al. Progress and challenges of artificial intelligence in lung cancer clinical translation. NPJ Precis Oncol. 2025;9(1):210.
Google Scholar
Wu L, Tian JY, Li MJ, Jiang F, Qiu LH, Yu WJ, et al. Validation of the 9th edition of the TNM staging system for limited-stage small cell lung cancer after resection: a multicenter study. Lung Cancer. 2025;200:108085.
Google Scholar
Nakao M, Suzuki A, Ichinose J, Matsuura Y, Okumura S, Ninomiya H, et al. Prognostic impact of the N2 subclassification and stage migration in the ninth edition of the TNM classification in surgically resected lung cancer. Lung Cancer. 2025;199:108073.
Google Scholar
Kim S, Ahn Y, Lee GD, Choi S, Kim HR, Kim YH, et al. Validation of the 9th tumor, node, and metastasis staging system for patients with surgically resected non-small cell lung cancer. Eur J Cancer. 2025. https://doi.org/10.1016/j.ejca.2025.115436.
Google Scholar
Ravella R, Feliciano EJG, Dee EC, Gomez DR, Iyengar P. Management of oligoprogressive and oligopersistent disease in advanced NSCLC. Clin Adv Hematol Oncol. 2025;23(1):40–50.
Google Scholar
Argentieri G, Valsecchi C, Petrella F, Jungblut L, Frauenfelder T, Del Grande F, et al. Implementation of the 9th TNM for lung cancer: practical insights for radiologists. Eur Radiol. 2025;35(7):4395–402.
Google Scholar
Gutiontov SI, Pitroda SP, Weichselbaum RR. Oligometastasis: past, present, future. Int J Radiat Oncol Biol Phys. 2020;108(3):530–8.
Google Scholar
Hellman S, Weichselbaum RR. Oligometastases. J Clin Oncol. 1995;13(1):8–10.
Google Scholar
Weichselbaum RR, Hellman S. Oligometastases revisited. Nat Rev Clin Oncol. 2011;8(6):378–82.
Google Scholar
Jin JN, Song ZB, Wang WX, Li Y, Wu SY. The impact of comprehensive local therapy on treatment outcomes of non-small cell lung cancer with solitary skeletal oligometastasis. J Bone Oncol. 2025; 52.
Dingemans AMC, Hendriks LEL, Berghmans T, Levy A, Hasan B, Faivre-Finn C, et al. Definition of synchronous oligometastatic non-small cell lung cancer-a consensus report. J Thorac Oncol. 2019;14(12):2109–19.
Google Scholar
Lievens Y, Guckenberger M, Gomez D, Hoyer M, Iyengar P, Kindts I, et al. Defining oligometastatic disease from a radiation oncology perspective: an ESTRO-ASTRO consensus document. Radiother Oncol. 2020;148:157–66.
Google Scholar
Christ SM, Pohl K, Muehlematter UJ, Heesen P, Kuhnis A, Willmann J, et al. Imaging-based prevalence of oligometastatic disease: a single-center cross-sectional study. Int J Radiat Oncol Biol Phys. 2022;114(4):596–602.
Google Scholar
Guckenberger M, Lievens Y, Bouma AB, Collette L, Dekker A, DeSouza NM, et al. Characterisation and classification of oligometastatic disease: a European Society for Radiotherapy and Oncology and European Organisation for Research and Treatment of Cancer consensus recommendation. Lancet Oncol. 2020;21(1):e18–28.
Google Scholar
Christ SM, Pohl K, Willmann J, Heesen P, Heusel A, Ahmadsei M, et al. Patterns of metastatic spread and tumor burden in unselected cancer patients using PET imaging: implications for the oligometastatic spectrum theory. Clin Transl Radiat Oncol. 2024;45:100724.
Google Scholar
Huellner MW, Barbosa FD, Husmann L, Pietsch CM, Mader CE, Burger IA, et al. TNM Staging of Non-Small Cell Lung Cancer: Comparison of PET/MR and PET/CT. J Nucl Med. 2016;57(1):21–6.
Google Scholar
Spaggiari L, Bertolaccini L, Facciolo F, Gallina FT, Rea F, Schiavon M, et al. A risk stratification scheme for synchronous oligometastatic non-small cell lung cancer developed by a multicentre analysis. Lung Cancer. 2021;154:29–35.
Google Scholar
Gomez DR, Yang TJ, Tsai CJ. Emerging paradigm of consolidative thoracic radiotherapy in oligometastatic NSCLC. Semin Radiat Oncol. 2021;31(2):120–3.
Google Scholar
Recondo G, Facchinetti F, Olaussen KA, Besse B, Friboulet L. Making the first move in EGFR-driven or ALK-driven NSCLC: first-generation or next-generation TKI? Nat Rev Clin Oncol. 2018;15(11):694–708.
Google Scholar
Yang Y, Liu H, Chen Y, Xiao N, Zheng Z, Liu H, et al. Liquid biopsy on the horizon in immunotherapy of non-small cell lung cancer: current status, challenges, and perspectives. Cell Death Dis. 2023;14(3):230.
Google Scholar
Pan K, Concannon K, Li J, Zhang J, Heymach JV, Le X. Emerging therapeutics and evolving assessment criteria for intracranial metastases in patients with oncogene-driven non-small-cell lung cancer. Nat Rev Clin Oncol. 2023. https://doi.org/10.1038/s41571-023-00808-4.
Google Scholar
Li Y, Yan B, He S. Advances and challenges in the treatment of lung cancer. Biomed Pharmacother. 2023;169:115891.
Google Scholar
Lee E, Kazerooni EA. Lung cancer screening. Semin Respir Crit Care Med. 2022. https://doi.org/10.1055/s-0042-1757885.
Google Scholar
Ma B, Wells A, Clark AM. The pan-therapeutic resistance of disseminated tumor cells: role of phenotypic plasticity and the metastatic microenvironment. Semin Cancer Biol. 2020;60:138–47.
Google Scholar
Tian T, Li YY, Li J, Xu HY, Fan H, Zhu J, Wang YS, Peng F, Gong YL, Du YJ et al: Immunotherapy for patients with advanced non-small cell lung cancer harboring oncogenic driver alterations other than EGFR: a multicenter real-world analysis. Transl Lung Cancer R. 2024; 13(4).
Wang LH, Liu X, Ren Y, Zhang JY, Chen JL, Zhou WL, et al. Cisplatin-enriching cancer stem cells confer multidrug resistance in non-small cell lung cancer via enhancing TRIB1/HDAC activity. Cell Death Dis. 2017. https://doi.org/10.1038/cddis.2016.409.
Google Scholar
Rotow J, Bivona TG. Understanding and targeting resistance mechanisms in NSCLC. Nat Rev Cancer. 2017;17(11):637–58.
Google Scholar
Song KA, Niederst MJ, Lochmann TL, Hata AN, Kitai H, Ham J, et al. Epithelial-to-mesenchymal transition antagonizes response to targeted therapies in lung cancer by suppressing BIM. Clin Cancer Res. 2018;24(1):197–208.
Google Scholar
Piotrowska Z, Isozaki H, Lennerz JK, Gainor JF, Lennes IT, Zhu VW, et al. Landscape of acquired resistance to Osimertinib in EGFR-mutant NSCLC and clinical validation of combined EGFR and RET inhibition with Osimertinib and BLU-667 for acquired RET fusion. Cancer Discov. 2018;8(12):1529–39.
Google Scholar
Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19(8):2240–7.
Google Scholar
Yap TA, Omlin A, de Bono JS. Development of therapeutic combinations targeting major cancer signaling pathways. J Clin Oncol. 2013;31(12):1592–605.
Google Scholar
Ju YS. Clonal history and genetic predictors of transformation into small cell carcinomas from lung adenocarcinomas. Cancer Sci. 2018;109:833–833.
Dimou A, Lo YC, Halling K, Mansfield AS. Small cell transformation in a patient with RET fusion positive lung adenocarcinoma on Pralsetinib. J Thorac Oncol. 2022;17(9):S414–S414.
Google Scholar
Fujita S, Masago K, Katakami N, Yatabe Y. Transformation to SCLC after treatment with the ALK inhibitor Alectinib. J Thorac Oncol. 2016;11(6):E67–72.
Google Scholar
Iams WT, Beckermann KE, Almodovar K, Hernandez J, Vnencak-Jones C, Lim LP, et al. Small cell lung cancer transformation as a mechanism of resistance to PD-1 therapy in KRAS-mutant lung adenocarcinoma: a report of two cases. J Thorac Oncol. 2019;14(3):E45–8.
Google Scholar
Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;3(75):75ra26.
Google Scholar
Schoenfeld AJ, Yu HA. The evolving landscape of resistance to Osimertinib. J Thorac Oncol. 2020;15(1):18–21.
Google Scholar
Lin JJ, Langenbucher A, Gupta P, Yoda S, Fetter IJ, Rooney M, et al. Small cell transformation of ROS1 fusion-positive lung cancer resistant to ROS1 inhibition. NPJ Precis Oncol. 2020. https://doi.org/10.1038/s41698-020-0127-9.
Google Scholar
Balla A, Khan F, Hampel KJ, Aisner DL, Sidiropoulos N. Small-cell transformation of ALK-rearranged non-small-cell adenocarcinoma of the lung. Cold Spring Harb Mol Case Stud. 2018. https://doi.org/10.1101/mcs.a002394.
Google Scholar
Fujimoto D, Akamatsu H, Morimoto T, Wakuda K, Sato Y, Kawa Y, et al. Histologic transformation of epidermal growth factor receptor-mutated lung cancer. Eur J Cancer. 2022;166:41–50.
Google Scholar
Schoenfeld AJ, Chan JM, Kubota D, Sato H, Rizvi H, Daneshbod Y, et al. Tumor analyses reveal squamous transformation and off-target alterations as early resistance mechanisms to first-line Osimertinib in EGFR-mutant lung cancer. Clin Cancer Res. 2020;26(11):2654–63.
Google Scholar
Quintanal-Villalonga A, Taniguchi H, Zhan YA, Hasan MM, Chavan SS, Meng F, et al. Comprehensive molecular characterization of lung tumors implicates AKT and MYC signaling in adenocarcinoma to squamous cell transdifferentiation. J Hematol Oncol. 2021;14(1):170.
Google Scholar
Awad MM, Liu S, Rybkin II, Arbour KC, Dilly J, Zhu VW, et al. Acquired resistance to KRAS(G12C) inhibition in cancer. N Engl J Med. 2021;384(25):2382–93.
Google Scholar
Shiba-Ishii A, Takemura N, Kawai H, Matsubara D. Histologic transformation of non-small-cell lung cancer in response to tyrosine kinase inhibitors: current knowledge of genetic changes and molecular mechanisms. Cancer Sci. 2024;115(7):2138–46.
Google Scholar
Rolfo C, Mack P, Scagliotti GV, Aggarwal C, Arcila ME, Barlesi F, et al. Liquid biopsy for advanced NSCLC: a consensus statement from the International Association for the Study of Lung Cancer. J Thorac Oncol. 2021;16(10):1647–62.
Google Scholar
Wei SC, Duffy CR, Allison JP. Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov. 2018;8(9):1069–86.
Google Scholar
Esposito M, Ganesan S, Kang Y. Emerging strategies for treating metastasis. Nat Cancer. 2021;2(3):258–70.
Google Scholar
Mariniello A, Borgeaud M, Weiner M, Frisone D, Kim F, Addeo A. Primary and acquired resistance to immunotherapy with checkpoint inhibitors in NSCLC: from bedside to bench and back. BioDrugs. 2025;39(2):215–35.
Google Scholar
Shire NJ, Klein AB, Golozar A, Collins JM, Fraeman KH, Nordstrom BL, et al. STK11 (LKB1) mutations in metastatic NSCLC: prognostic value in the real world. PLoS ONE. 2020;15(9):e0238358.
Google Scholar
Mazieres J, Drilon A, Lusque A, Mhanna L, Cortot AB, Mezquita L, et al. Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry. Ann Oncol. 2019;30(8):1321–8.
Google Scholar
Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gümüs M, Mazières J, et al. Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer. New Engl J Med. 2018;379(21):2040–51.
Google Scholar
Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell. 2017;168(4):707–23.
Google Scholar
Ahn MJ, Tanaka K, Paz-Ares L, Cornelissen R, Girard N, Pons-Tostivint E, et al. Datopotamab Deruxtecan Versus Docetaxel for Previously Treated Advanced or Metastatic Non-Small Cell Lung Cancer: The Randomized, Open-Label Phase III TROPION-Lung01 Study. J Clin Oncol. 2025;43(3):260–72.
Google Scholar
Paz-Ares LG, Juan-Vidal O, Mountzios GS, Felip E, Reinmuth N, de Marinis F, Girard N, Patel VM, Takahama T, Owen SP et al: Sacituzumab Govitecan Versus Docetaxel for Previously Treated Advanced or Metastatic Non-Small Cell Lung Cancer: The Randomized, Open-Label Phase III EVOKE-01 Study. J Clin Oncol. 2024; 42(24).
Marcus L, Fashoyin-Aje LA, Donoghue M, Yuan MD, Rodriguez L, Gallagher PS, et al. FDA approval summary: pembrolizumab for the treatment of tumor mutational burden-high solid for tumors. Clin Cancer Res. 2021;27(17):4685–9.
Google Scholar
Yarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and response rate to PD-1 inhibition. New Engl J Med. 2017;377(25):2500–1.
Google Scholar
Zheng M. Tumor mutation burden for predicting immune checkpoint blockade response: the more, the better. J Immunother Cancer. 2022. https://doi.org/10.1136/jitc-2021-003087.
Google Scholar
Jardim DL, Goodman A, Gagliato DD, Kurzrock R. The challenges of tumor mutational burden as an immunotherapy biomarker. Cancer Cell. 2021;39(2):154–73.
Google Scholar
Shao MM, Xu YP, Zhang JJ, Mao M, Wang MC. Tumor mutational burden as a predictive biomarker for non-small cell lung cancer treated with immune checkpoint inhibitors of PD-1/PD-L1. Clin Transl Oncol. 2024;26(6):1446–58.
Google Scholar
McGrail DJ, Pilié PG, Rashid NU, Voorwerk L, Slagter M, Kok M, et al. High tumor mutation burden fails to predict immune checkpoint blockade response across all cancer types. Ann Oncol. 2021;32(5):661–72.
Google Scholar
Niknafs N, Balan A, Cherry C, Hummelink K, Monkhorst K, Shao XM, et al. Persistent mutation burden drives sustained anti-tumor immune responses. Nat Med. 2023;29(2):440–9.
Google Scholar
Schoenfeld AJ, Antonia SJ, Awad MM, Felip E, Gainor J, Gettinger SN, et al. Clinical definition of acquired resistance to immunotherapy in patients with metastatic non-small-cell lung cancer. Ann Oncol. 2021;32(12):1597–607.
Google Scholar
Rizvi N, Ademuyiwa FO, Cao ZA, Chen HX, Ferris RL, Goldberg SB, et al. Society for immunotherapy of cancer (SITC) consensus definitions for resistance to combinations of immune checkpoint inhibitors with chemotherapy. J Immunother Cancer. 2023. https://doi.org/10.1136/jitc-2022-005920.
Google Scholar
Bonanno L, Dal Maso A, Pavan A, Zulato E, Calvetti L, Pasello G, et al. Liquid biopsy and non-small cell lung cancer: are we looking at the tip of the iceberg? Br J Cancer. 2022;127(3):383–93.
Google Scholar
Kluger HM, Tawbi HA, Ascierto ML, Bowden M, Callahan MK, Cha E, et al. Defining tumor resistance to PD-1 pathway blockade: recommendations from the first meeting of the SITC immunotherapy resistance taskforce. J Immunother Cancer. 2020. https://doi.org/10.1136/jitc-2019-000398.
Google Scholar
Kluger H, Barrett JC, Gainor JF, Hamid O, Hurwitz M, LaVallee T, et al. Society for immunotherapy of cancer (SITC) consensus definitions for resistance to combinations of immune checkpoint inhibitors. J Immunother Cancer. 2023. https://doi.org/10.1136/jitc-2022-005921.
Google Scholar
Passaro A, Brahmer J, Antonia S, Mok T, Peters S. Managing resistance to immune checkpoint inhibitors in lung cancer: treatment and novel strategies. J Clin Oncol. 2022;40(6):598–610.
Google Scholar
Prelaj A, Ganzinelli M, Trovo F, Roisman LC, Pedrocchi ALG, Kosta S, et al. The EU-funded I(3)LUNG project: integrative science, intelligent data platform for individualized lung cancer care with immunotherapy. Clin Lung Cancer. 2023;24(4):381–7.
Google Scholar
Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018;378(2):113–25.
Google Scholar
Peters S, Camidge DR, Shaw AT, Gadgeel S, Ahn JS, Kim DW, et al. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med. 2017;377(9):829–38.
Google Scholar
Lisberg A, Cummings A, Goldman JW, Bornazyan K, Reese N, Wang T, et al. A phase II study of pembrolizumab in EGFR-mutant, PD-L1+, tyrosine kinase inhibitor naive patients with advanced NSCLC. J Thorac Oncol. 2018;13(8):1138–45.
Google Scholar
Ahn MJ, Cho BC, Ou X, Walding A, Dymond AW, Ren S, et al. Osimertinib plus durvalumab in patients with EGFR-mutated, advanced NSCLC: a phase 1b, open-label, multicenter trial. J Thorac Oncol. 2022;17(5):718–23.
Google Scholar
Cui W, Cotter C, Sreter KB, Heelan K, Creamer D, Basu TN, et al. Case of fatal immune-related skin toxicity from sequential use of Osimertinib after Pembrolizumab: lessons for drug sequencing in never-smoking non-small-cell lung cancer. JCO Oncol Pract. 2020;16(12):842–4.
Google Scholar
Creelan BC, Yeh TC, Kim SW, Nogami N, Kim DW, Chow LQM, et al. A phase 1 study of gefitinib combined with durvalumab in EGFR TKI-naive patients with EGFR mutation-positive locally advanced/metastatic non-small-cell lung cancer. Br J Cancer. 2021;124(2):383–90.
Google Scholar
Overbey EG, Kim J, Tierney BT, Park J, Houerbi N, Lucaci AG, et al. The Space Omics and Medical Atlas (SOMA) and international astronaut biobank. Nature. 2024;632(8027):1145–54.
Google Scholar
Wang XY, Wu YN, Gu JH, Xu J. Tumor-associated macrophages in lung carcinoma: from mechanism to therapy. Pathol Res Pract. 2022. https://doi.org/10.1016/j.prp.2021.153747.
Google Scholar
Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009;9(3):162–74.
Google Scholar
Tay C, Tanaka A, Sakaguchi S. Tumor-infiltrating regulatory t cells as targets of cancer immunotherapy. Cancer Cell. 2023;41(3):450–65.
Google Scholar
Xing S, Hu K, Wang Y. Tumor immune microenvironment and immunotherapy in non-small cell lung cancer: update and new challenges. Aging Dis. 2022;13(6):1615–32.
Google Scholar
Linette GP, Carreno BM. Tumor-infiltrating lymphocytes in the checkpoint inhibitor era. Curr Hematol Malig Rep. 2019;14(4):286–91.
Google Scholar
Chen B, Li H, Liu C, Xiang X, Wang S, Wu A, et al. Prognostic value of the common tumour-infiltrating lymphocyte subtypes for patients with non-small cell lung cancer: a meta-analysis. PLoS ONE. 2020;15(11):e0242173.
Google Scholar
Korkolopoulou P, Kaklamanis L, Pezzella F, Harris AL, Gatter KC. Loss of antigen-presenting molecules (MHC class I and TAP-1) in lung cancer. Br J Cancer. 1996;73(2):148–53.
Google Scholar
Schutt P, Schutt B, Switala M, Bauer S, Stamatis G, Opalka B, et al. Prognostic relevance of soluble human leukocyte antigen-G and total human leukocyte antigen class I molecules in lung cancer patients. Hum Immunol. 2010;71(5):489–95.
Google Scholar
Lin A, Zhu CC, Chen HX, Chen BF, Zhang X, Zhang JG, et al. Clinical relevance and functional implications for human leucocyte antigen-g expression in non-small-cell lung cancer. J Cell Mol Med. 2010;14(9):2318–29.
Google Scholar
Chen YB, Mu CY, Huang JA. Clinical significance of programmed death-1 ligand-1 expression in patients with non-small cell lung cancer: a 5-year-follow-up study. Tumori. 2012;98(6):751–5.
Google Scholar
Konishi J, Yamazaki K, Azuma M, Kinoshita I, Dosaka-Akita H, Nishimura M. B7–h1 expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression. Clin Cancer Res. 2004;10(15):5094–100.
Google Scholar
Zhang LB, Chen YH, Wang H, Xu ZY, Wang Y, Li SX, et al. Massive PD-L1 and CD8 double positive TILs characterize an immunosuppressive microenvironment with high mutational burden in lung cancer. J Immunother Cancer. 2021. https://doi.org/10.1136/jitc-2021-002356.
Google Scholar
Skoulidis F, Byers LA, Diao L, Papadimitrakopoulou VA, Tong P, Izzo J, et al. Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities. Cancer Discov. 2015;5(8):860–77.
Google Scholar
Skoulidis F, Goldberg ME, Greenawalt DM, Hellmann MD, Awad MM, Gainor JF, et al. STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma. Cancer Discov. 2018;8(7):822–35.
Google Scholar
Kitajima S, Ivanova E, Guo S, Yoshida R, Campisi M, Sundararaman SK, et al. Suppression of STING associated with LKB1 loss in KRAS-driven lung cancer. Cancer Discov. 2019;9(1):34–45.
Google Scholar
Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJM, Robert L, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515(7528):568.
Google Scholar
Mollaoglu G, Jones A, Wait SJ, Mukhopadhyay A, Jeong S, Arya R, Camolotto SA, Mosbruger TL, Stubben CJ, Conley CJ et al: The Lineage-Defining Transcription Factors SOX2 and NKX2–1 Determine Lung Cancer Cell Fate and Shape the Tumor Immune Microenvironment. Immunity. 2018; 49(4):764–779 e769.
DuCote TJ, Naughton KJ, Skaggs EM, Bocklage TJ, Allison DB, Brainson CF. Using artificial intelligence to identify tumor microenvironment heterogeneity in non-small cell lung cancers. Lab Invest. 2023. https://doi.org/10.1016/j.labinv.2023.100176.
Google Scholar
Zhang JH, Huang YH, Han YC, Dong D, Cao YQ, Chen X, et al. Immune microenvironment heterogeneity of concurrent adenocarcinoma and squamous cell carcinoma in multiple primary lung cancers. NPJ Precis Oncol. 2024. https://doi.org/10.1038/s41698-024-00548-3.
Google Scholar
Eruslanov EB, Bhojnagarwala PS, Quatromoni JG, Stephen TL, Ranganathan A, Deshpande C, et al. Tumor-associated neutrophils stimulate T cell responses in early-stage human lung cancer. J Clin Invest. 2014;124(12):5466–80.
Google Scholar
Ferone G, Song J-Y, Sutherland KD, Bhaskaran R, Monkhorst K, Lambooij J-P, et al. SOX2 is the determining oncogenic switch in promoting lung squamous cell carcinoma from different cells of origin. Cancer Cell. 2016;30(4):519–32.
Google Scholar
Xu C, Fillmore CM, Koyama S, Wu H, Zhao Y, Chen Z, et al. Loss of Lkb1 and Pten leads to lung squamous cell carcinoma with elevated PD-L1 expression. Cancer Cell. 2014;25(5):590–604.
Google Scholar
Busch SE, Hanke ML, Kargl J, Metz HE, MacPherson D, Houghton AM. Lung cancer subtypes generate unique immune responses. J Immunol. 2016;197(11):4493–503.
Google Scholar
Koyama S, Akbay EA, Li YY, Aref AR, Skoulidis F, Herter-Sprie GS, et al. STK11/LKB1 deficiency promotes neutrophil recruitment and proinflammatory cytokine production to suppress T-cell activity in the lung tumor microenvironment. Cancer Res. 2016;76(5):999–1008.
Google Scholar
Nagaraj AS, Lahtela J, Hemmes A, Pellinen T, Blom S, Devlin JR, et al. Cell of origin links histotype spectrum to immune microenvironment diversity in non-small-cell lung cancer driven by mutant Kras and loss of Lkb1. Cell Rep. 2017;18(3):673–84.
Google Scholar
Giacobbe A, Abate-Shen C. Modeling metastasis in mice: a closer look. Trends Cancer. 2021;7(10):916–29.
Google Scholar
Kähkönen TE, Halleen JM, Bernoulli J. Immunotherapies and metastatic cancers: understanding utility and predictivity of human immune cell engrafted mice in preclinical drug development. Cancers. 2020;12(6):1615.
Google Scholar
Wakefield L, Agarwal S, Tanner K. Preclinical models for drug discovery for metastatic disease. Cell. 2023;186(8):1792–813.
Google Scholar
Exposito F, Connolly KA, Tang T, Chiorazzi M, Hunt BG, Cardenas JJ, et al. Preclinical models of solid cancers for testing cancer immunotherapies. Annu Rev Cancer Biol. 2025;9:285–305.
Google Scholar
Shi RS, Radulovich N, Ng C, Liu N, Notsuda H, Cabanero M, et al. Organoid cultures as preclinical models of non-small cell lung cancer. Clin Cancer Res. 2020;26(5):1162–74.
Google Scholar
Suvilesh KN, Nussbaum YI, Radhakrishnan V, Manjunath Y, Avella DM, Staveley-O’Carroll KF, Kimchi ET, Chaudhuri AA, Shyu CR, Li GF et al: Tumorigenic circulating tumor cells from xenograft mouse models of non-metastatic NSCLC patients reveal distinct single cell heterogeneity and drug responses. Mol Cancer 2022, 21(1).
Liu Y, Wu W, Cai C, Zhang H, Shen H, Han Y. Patient-derived xenograft models in cancer therapy: technologies and applications. Signal Transduct Target Ther. 2023;8(1):160.
Google Scholar
Jiang M, Tu RF, Pan YW, Cui YX, Qi X, Qin HY, et al. Patient-derived organoids and mini-PDX for predicting METN375S-mutated lung cancer patient clinical therapeutic response. Heliyon. 2024. https://doi.org/10.1016/j.heliyon.2024.e37884.
Google Scholar
Zanella ER, Grassi E, Trusolino L. Towards precision oncology with patient-derived xenografts. Nat Rev Clin Oncol. 2022;19(11):719–32.
Google Scholar
Wang J, Chen C, Wang L, Xie MJ, Ge XY, Wu SF, et al. Patient-derived tumor organoids: new progress and opportunities to facilitate precision cancer immunotherapy. Front Oncol. 2022. https://doi.org/10.3389/fonc.2022.872531.
Google Scholar
Gazdar AF, Hirsch FR, Minna JD. From mice to men and back: an assessment of preclinical model systems for the study of lung cancers. J Thorac Oncol. 2016;11(3):287–99.
Google Scholar
Safari R, Meuwissen R. Practical use of advanced mouse models for lung cancer. Methods Mol Biol. 2015;1267:93–124.
Google Scholar
Olive KP, Tuveson DA, Ruhe ZC, Yin B, Willis NA, Bronson RT, et al. Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome. Cell. 2004;119(6):847–60.
Google Scholar
Winslow MM, Dayton TL, Verhaak RG, Kim-Kiselak C, Snyder EL, Feldser DM, et al. Suppression of lung adenocarcinoma progression by Nkx2-1. Nature. 2011;473(7345):101–4.
Google Scholar
Rongvaux A, Takizawa H, Strowig T, Willinger T, Eynon EE, Flavell RA, et al. Human hemato-lymphoid system mice: current use and future potential for medicine. Annu Rev Immunol. 2013;31:635–74.
Google Scholar
Ye WJ, Chen QF. Potential applications and perspectives of humanized mouse models. Annu Rev Anim Biosci. 2022;10:395–417.
Google Scholar
Moquin-Beaudry G, Benabdallah B, Maggiorani D, Le O, Li Y, Colas C, et al. Autologous humanized mouse models of iPSC-derived tumors enable characterization and modulation of cancer-immune cell interactions. Cell Rep Methods. 2022;2(1):100153.
Google Scholar
Ishikawa F, Yasukawa M, Lyons B, Yoshida S, Miyamoto T, Yoshimoto G, et al. Development of functional human blood and immune systems in NOD/SCID/IL2 receptor gamma chain(null) mice. Blood. 2005;106(5):1565–73.
Google Scholar
Yao JL, Ly D, Dervovic D, Fang LN, Lee JB, Kang H, et al. Human double negative T cells target lung cancer via ligand-dependent mechanisms that can be enhanced by IL-15. J Immunother Cancer. 2019. https://doi.org/10.1186/s40425-019-0507-2.
Google Scholar
Meraz IM, Majidi M, Song RD, Meng F, Gao LH, Wang Q, et al. NPRL2 gene therapy induces effective antitumor immunity in KRAS/STK11 mutant anti-PD1 resistant metastatic non-small cell lung cancer (NSCLC) in a humanized mouse model. Elife. 2025. https://doi.org/10.7554/eLife.98258.
Google Scholar
Shultz LD, Ishikawa F, Greiner DL. Humanized mice in translational biomedical research. Nat Rev Immunol. 2007;7(2):118–30.
Google Scholar
Rongvaux A, Willinger T, Martinek J, Strowig T, Gearty SV, Teichmann LL, et al. Development and function of human innate immune cells in a humanized mouse model. Nat Biotechnol. 2014;32(4):364–72.
Google Scholar
Ravi R, Noonan KA, Pham V, Bedi R, Zhavoronkov A, Ozerov IV, et al. Bifunctional immune checkpoint-targeted antibody-ligand traps that simultaneously disable TGFβ enhance the efficacy of cancer immunotherapy. Nat Commun. 2018. https://doi.org/10.1038/s41467-017-02696-6.
Google Scholar
Chuprin J, Buettner H, Seedhom MO, Greiner DL, Keck JG, Ishikawa F, et al. Humanized mouse models for immuno-oncology research. Nat Rev Clin Oncol. 2023;20(3):192–206.
Google Scholar
Pan JR, Zhang L, Huang ZB, Zhao DL, Li H, Fu YA, et al. Strategies for generating mouse model resources of human disease. Protein Cell. 2023;14(12):866–70.
Google Scholar
Wege AK, Ernst W, Eckl J, Frankenberger B, Vollmann-Zwerenz A, Mannel DN, et al. Humanized tumor mice–a new model to study and manipulate the immune response in advanced cancer therapy. Int J Cancer. 2011;129(9):2194–206.
Google Scholar
Tomasetti C, Levy D. Role of symmetric and asymmetric division of stem cells in developing drug resistance. P Natl Acad Sci USA. 2010;107(39):16766–71.
Google Scholar
Lord CJ, Ashworth A. The DNA damage response and cancer therapy. Nature. 2012;481(7381):287–94.
Google Scholar
Saini V, Shoemaker RH. Potential for therapeutic targeting of tumor stem cells. Cancer Sci. 2010;101(1):16–21.
Google Scholar
Vagnozzi RJ, Sargent MA, Lin SJ, Palpant NJ, Murry CE, Molkentin JD. Genetic lineage tracing of Sca-1(+) cells reveals endothelial but not myogenic contribution to the murine heart. Circulation. 2018;138(25):2931–9.
Google Scholar
Zhang CY, Sui YX, Liu S, Yang M. In vitro and in vivo experimental models for cancer immunotherapy study. Curr Res Biotechnol. 2024; 7.
Khamarudin F, Muhamad M, Ibahim MJ, Zain WNIWM, Aziz MA, Ridzuan NRA, Ab-Rahim S: Establishment of humanised xenograft models as in vivo study for lung metastasis of osteosarcoma. Immunother Adv. 2024; 4(1).
Yoshida R, Saigi M, Tani T, Springer BF, Shibata H, Kitajima S, et al. MET-induced CD73 restrains STING-mediated immunogenicity of EGFR-mutant lung cancer. Cancer Res. 2022;82(21):4079–92.
Google Scholar
Meraz IM, Majidi M, Shao R, Meng F, Ha MJ, Shpall E, et al. TUSC2 immunogene enhances efficacy of chemo-immuno combination on KRAS/LKB1 mutant NSCLC in humanized mouse model. Commun Biol. 2022;5(1):167.
Google Scholar
Cao B, Liu M, Wang L, Zhu K, Cai M, Chen X, et al. Remodelling of tumour microenvironment by microwave ablation potentiates immunotherapy of AXL-specific CAR T cells against non-small cell lung cancer. Nat Commun. 2022;13(1):6203. https://doi.org/10.1038/s41467-022-33968-5
Liu M, Wang X, Li W, Yu XF, Flores-Villanueva P, Xu-Monette ZJY, Li L, Zhang MZ, Young KH, Ma XD et al: Targeting PD-L1 in non-small cell lung cancer using CAR T cells. Oncogenesis. 2020; 9(8). https://doi.org/10.1038/s41389-020-00257-z
Meraz IM, Majidi M, Meng F, Shao R, Ha MJ, Neri S, et al. An improved patient-derived xenograft humanized mouse model for evaluation of lung cancer immune responses. Cancer Immunol Res. 2019;7(8):1267–79.
Google Scholar
Wang M, Yao LC, Cheng M, Cai D, Martinek J, Pan CX, et al. Humanized mice in studying efficacy and mechanisms of PD-1-targeted cancer immunotherapy. FASEB J. 2018;32(3):1537–49.
Google Scholar
Li H, Huang Y, Jiang DQ, Cui LZ, He Z, Wang C, et al. Antitumor activity of EGFR-specific CAR T cells against non-small-cell lung cancer cells in vitro and in mice. Cell Death Dis. 2018;9(2):177. https://doi.org/10.1038/s41419-017-0238-6
Google Scholar