Xu M, Xu H, Ling YW, Liu JJ, Song P, Fang ZQ, Yue ZS, Duan JL, He F, Wang L. Neutrophil extracellular traps-triggered hepatocellular senescence exacerbates lipotoxicity in non-alcoholic steatohepatitis. J Adv Res. 2025;S2090–1232(25):00175–4. https://doi.org/10.1016/j.jare.2025.03.015. Epub ahead of print. PMID: 40068761.
Google Scholar
Zhang H, Wang Y, Qu M, Li W, Wu D, Cata JP, et al. Neutrophil, neutrophil extracellular traps and endothelial cell dysfunction in sepsis. Clin Transl Med. 2023;13(1):e1170. https://doi.org/10.1002/ctm2.1170.
Google Scholar
Ma Y, Wei J, He W, Ren J. Neutrophil extracellular traps in cancer. MedComm. 2024;5(8):e647. https://doi.org/10.1002/mco2.647.
Google Scholar
Petretto A, Bruschi M, Pratesi F, Croia C, Candiano G, Ghiggeri G, et al. Neutrophil extracellular traps (NET) induced by different stimuli: a comparative proteomic analysis. PLoS ONE. 2019;14(7):e0218946. https://doi.org/10.1371/journal.pone.0218946.
Google Scholar
Jaillon S, Ponzetta A, Di Mitri D, Santoni A, Bonecchi R, Mantovani A. Neutrophil diversity and plasticity in tumour progression and therapy. Nat Rev Cancer. 2020;20(9):485–503. https://doi.org/10.1038/s41568-020-0281-y.
Google Scholar
Shaul ME, Fridlender ZG. Tumour-associated neutrophils in patients with cancer. Nat Rev Clin Oncol. 2019;16(10):601–20. https://doi.org/10.1038/s41571-019-0222-4.
Google Scholar
Ozveren A, Erdogan AP, Ekinci F. The inflammatory prognostic index as a potential predictor of prognosis in metastatic gastric cancer. Sci Rep. 2023;13(1):7755. https://doi.org/10.1038/s41598-023-34778-5. PMID: 37173358; PMCID: PMC10182084.
Google Scholar
Coffelt SB, Wellenstein MD, de Visser KE. Neutrophils in cancer: neutral no more. Nat Rev Cancer. 2016;16(7):431–46. https://doi.org/10.1038/nrc.2016.52.
Google Scholar
Mantovani A, Cassatella MA, Costantini C, Jaillon S. Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol. 2011;11(8):519–31. https://doi.org/10.1038/nri3024. PMID: 21785456.
Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140(6):883–99. https://doi.org/10.1016/j.cell.2010.01.025.
Google Scholar
Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol. 2013;13(3):159–75. https://doi.org/10.1038/nri3399.
Google Scholar
Borregaard N. Neutrophils, from marrow to microbes. Immunity. 2010;33(5):657–70. https://doi.org/10.1016/j.immuni.2010.11.011.
Google Scholar
Mantovani A, Cassatella MA, Costantini C, Jaillon S. Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol. 2011;11(8):519–31. https://doi.org/10.1038/nri3024.
Google Scholar
Adrover JM, McDowell SAC, He XY, Quail DF, Egeblad M. NETworking with cancer: the bidirectional interplay between cancer and neutrophil extracellular traps. Cancer Cell. 2023;41(3):505–26. https://doi.org/10.1016/j.ccell.2023.02.001.
Google Scholar
Papayannopoulos V. Neutrophil extracellular traps in immunity and disease. Nat Rev Immunol. 2018;18(2):134–47. https://doi.org/10.1038/nri.2017.105.
Google Scholar
Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, et al. Neutrophil extracellular traps kill bacteria. Science. 2004;303(5663):1532–5. https://doi.org/10.1126/science.1092385.
Google Scholar
Fuchs TA, Abed U, Goosmann C, Hurwitz R, Schulze I, Wahn V, et al. Novel cell death program leads to neutrophil extracellular traps. J Cell Biol. 2007;176(2):231–41. https://doi.org/10.1083/jcb.200606027.
Google Scholar
Herre M, Cedervall J, Mackman N, Olsson AK. Neutrophil extracellular traps in the pathology of cancer and other inflammatory diseases. Physiol Rev. 2023;103(1):277–312. https://doi.org/10.1152/physrev.00062.2021.
Google Scholar
Leung HHL, Perdomo J, Ahmadi Z, Yan F, McKenzie SE, Chong BH. Inhibition of NADPH oxidase blocks NETosis and reduces thrombosis in heparin-induced thrombocytopenia. Blood Adv. 2021;5(23):5439–51. https://doi.org/10.1182/bloodadvances.2020003093.
Google Scholar
Chen KW, Monteleone M, Boucher D, Sollberger G, Ramnath D, Condon ND, et al. Noncanonical inflammasome signaling elicits gasdermin D-dependent neutrophil extracellular traps. Sci Immunol. 2018;3(26):eaar6676. https://doi.org/10.1126/sciimmunol.aar6676.
Google Scholar
Chi Z, Chen S, Yang D, Cui W, Lu Y, Wang Z, et al. Gasdermin d-mediated metabolic crosstalk promotes tissue repair. Nature. 2024;634(8036):1168–77. https://doi.org/10.1038/s41586-024-08022-7.
Google Scholar
Zhang J, Yu Q, Jiang D, Yu K, Yu W, Chi Z, Chen S, Li M, Yang D, Wang Z, Xu T, Guo X, Zhang K, Fang H, Ye Q, He Y, Zhang X, Wang D. Epithelial Gasdermin D shapes the host-microbial interface by driving mucus layer formation. Sci Immunol. 2022;7(68):eabk2092. https://doi.org/10.1126/sciimmunol.abk2092. Epub 2022 Feb 4. PMID: 35119941.
Google Scholar
Fontana P, Du G, Zhang Y, Zhang H, Vora SM, Hu JJ, Shi M, Tufan AB, Healy LB, Xia S, Lee DJ, Li Z, Baldominos P, Ru H, Luo HR, Agudo J, Lieberman J, Wu H. Small-molecule GSDMD agonism in tumors stimulates antitumor immunity without toxicity. Cell. 2024;187(22):6165–e618122. Epub 2024 Sep 6. PMID: 39243763.
Google Scholar
Bianchi M, Hakkim A, Brinkmann V, Siler U, Seger RA, Zychlinsky A, et al. Restoration of NET formation by gene therapy in CGD controls aspergillosis. Blood. 2009;114(13):2619–22. https://doi.org/10.1182/blood-2009-05-221606.
Google Scholar
Ermert D, Urban CF, Laube B, Goosmann C, Zychlinsky A, Brinkmann V. Mouse neutrophil extracellular traps in microbial infections. J Innate Immun. 2009;1(3):181–93. https://doi.org/10.1159/000205281.
Google Scholar
Pilsczek FH, Salina D, Poon KK, Fahey C, Yipp BG, Sibley CD, et al. A novel mechanism of rapid nuclear neutrophil extracellular trap formation in response to Staphylococcus aureus. J Immunol. 2010;185(12):7413–25. https://doi.org/10.4049/jimmunol.1000675.
Google Scholar
Byrd AS, O’Brien XM, Johnson CM, Lavigne LM, Reichner JS. An extracellular matrix-based mechanism of rapid neutrophil extracellular trap formation in response to Candida albicans. J Immunol. 2013;190(8):4136–48. https://doi.org/10.4049/jimmunol.1202671.
Google Scholar
Parker H, Dragunow M, Hampton MB, Kettle AJ, Winterbourn CC. Requirements for NADPH oxidase and myeloperoxidase in neutrophil extracellular trap formation differ depending on the stimulus. J Leukoc Biol. 2012;92(4):841–9. https://doi.org/10.1189/jlb.1211601.
Google Scholar
Douda DN, Khan MA, Grasemann H, Palaniyar N. SK3 channel and mitochondrial ROS mediate NADPH oxidase-independent NETosis induced by calcium influx. Proc Natl Acad Sci U S A. 2015;112(9):2817–22. https://doi.org/10.1073/pnas.1414055112.
Google Scholar
Hosseinzadeh A, Thompson PR, Segal BH, Urban CF. Nicotine induces neutrophil extracellular traps. J Leukoc Biol. 2016;100(5):1105–12. https://doi.org/10.1189/jlb.3AB0815-379RR.
Google Scholar
Castanheira FVS, Kubes P. Neutrophils and NETs in modulating acute and chronic inflammation. Blood. 2019;133(20):2178–85. https://doi.org/10.1182/blood-2018-11-844530.
Google Scholar
Li M, Lin C, Deng H, Strnad J, Bernabei L, Vogl DT, et al. A novel peptidylarginine deiminase 4 (PAD4) inhibitor BMS-P5 blocks formation of neutrophil extracellular traps and delays progression of multiple myeloma. Mol Cancer Ther. 2020;19(7):1530–8. https://doi.org/10.1158/1535-7163.MCT-19-1020.
Google Scholar
Papayannopoulos V, Metzler KD, Hakkim A, Zychlinsky A. Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps. J Cell Biol. 2010;191(3):677–91. https://doi.org/10.1083/jcb.201006052.
Google Scholar
Metzler KD, Fuchs TA, Nauseef WM, Reumaux D, Roesler J, Schulze I, et al. Myeloperoxidase is required for neutrophil extracellular trap formation: implications for innate immunity. Blood. 2011;117(3):953–9. https://doi.org/10.1182/blood-2010-06-290171.
Google Scholar
Knight JS, Zhao W, Luo W, Subramanian V, O’Dell AA, Yalavarthi S, et al. Peptidylarginine deiminase inhibition is immunomodulatory and vasculoprotective in murine lupus. J Clin Invest. 2013;123(7):2981–93. https://doi.org/10.1172/JCI67390.
Google Scholar
Guiducci E, Lemberg C, Küng N, Schraner E, Theocharides APA, LeibundGut-Landmann S. Candida albicans-induced NETosis is independent of peptidylarginine deiminase 4. Front Immunol. 2018;9:1573. https://doi.org/10.3389/fimmu.2018.01573.
Google Scholar
Claushuis TAM, van der Donk LEH, Luitse AL, van Veen HA, van der Wel NN, van Vught LA, Roelofs JJTH, de Boer OJ, Lankelma JM, Boon L, de Vos AF, van ‘t Veer C, van der Poll T. Role of peptidylarginine deiminase 4 in neutrophil extracellular trap formation and host defense during Klebsiella pneumoniae-Induced Pneumonia-Derived sepsis. J Immunol. 2018;201(4):1241–52. https://doi.org/10.4049/jimmunol.1800314. Epub 2018 Jul 9. PMID: 29987161.
Google Scholar
Warnatsch A, Ioannou M, Wang Q, Papayannopoulos V. Inflammation. Neutrophil extracellular traps license macrophages for cytokine production in atherosclerosis. Science. 2015;349(6245):316–20. https://doi.org/10.1126/science.aaa8064. Epub 2015 Jul 16. PMID: 26185250; PMCID: PMC4854322.
Google Scholar
Branzk N, Lubojemska A, Hardison SE, Wang Q, Gutierrez MG, Brown GD, et al. Neutrophils sense microbe size and selectively release neutrophil extracellular traps in response to large pathogens. Nat Immunol. 2014;15(11):1017–25. https://doi.org/10.1038/ni.2987.
Google Scholar
Hakkim A, Fuchs TA, Martinez NE, Hess S, Prinz H, Zychlinsky A, Waldmann H. Activation of the Raf-MEK-ERK pathway is required for neutrophil extracellular trap formation. Nat Chem Biol. 2011;7(2):75–7. https://doi.org/10.1038/nchembio.496. Epub 2010 Dec 19. PMID: 21170021.
Google Scholar
Yipp BG, Petri B, Salina D, Jenne CN, Scott BN, Zbytnuik LD, Pittman K, Asaduzzaman M, Wu K, Meijndert HC, Malawista SE, de Boisfleury Chevance A, Zhang K, Conly J, Kubes P. Infection-induced NETosis is a dynamic process involving neutrophil multitasking in vivo. Nat Med. 2012;18(9):1386–93. https://doi.org/10.1038/nm.2847. PMID: 22922410; PMCID: PMC4529131.
Google Scholar
Yipp BG, Kubes P. NETosis: how vital is it? Blood. 2013;122(16):2784–94. https://doi.org/10.1182/blood-2013-04-457671.
Google Scholar
Wang Y, Li M, Stadler S, Correll S, Li P, Wang D, et al. Histone hypercitrullination mediates chromatin decondensation and neutrophil extracellular trap formation. J Cell Biol. 2009;184(2):205–13. https://doi.org/10.1083/jcb.200806072.
Google Scholar
McDonald B, Urrutia R, Yipp BG, Jenne CN, Kubes P. Intravascular neutrophil extracellular traps capture bacteria from the bloodstream during sepsis. Cell Host Microbe. 2012;12(3):324–33. https://doi.org/10.1016/j.chom.2012.06.011.
Google Scholar
Jorch SK, Kubes P. An emerging role for neutrophil extracellular traps in noninfectious disease. Nat Med. 2017;23(3):279–87. https://doi.org/10.1038/nm.4294.
Google Scholar
Kim J, Kim HS, Chung JH. Molecular mechanisms of mitochondrial DNA release and activation of the cGAS-STING pathway. Exp Mol Med. 2023;55(3):510–9. https://doi.org/10.1038/s12276-023-00965-7.
Google Scholar
Yousefi S, Gold JA, Andina N, Lee JJ, Kelly AM, Kozlowski E, et al. Catapult-like release of mitochondrial DNA by eosinophils contributes to antibacterial defense. Nat Med. 2008;14(9):949–53. https://doi.org/10.1038/nm.1855.
Google Scholar
McIlroy DJ, Jarnicki AG, Au GG, Lott N, Smith DW, Hansbro PM, Balogh ZJ. Mitochondrial DNA neutrophil extracellular traps are formed after trauma and subsequent surgery. J Crit Care. 2014;29(6):1133.e1-5. https://doi.org/10.1016/j.jcrc.2014.07.013. Epub 2014 Jul 22. PMID: 25128442.
Google Scholar
Lood C, Blanco LP, Purmalek MM, Carmona-Rivera C, De Ravin SS, Smith CK, et al. Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease. Nat Med. 2016;22(2):146–53. https://doi.org/10.1038/nm.4027.
Google Scholar
Yousefi S, Mihalache C, Kozlowski E, Schmid I, Simon HU. Viable neutrophils release mitochondrial DNA to form neutrophil extracellular traps. Cell Death Differ. 2009;16(11):1438–44. https://doi.org/10.1038/cdd.2009.96.
Google Scholar
Zhang Y, Guo F, Wang Y. Hypoxic tumor microenvironment: destroyer of natural killer cell function. Chin J Cancer Res. 2024;36(2):138–50. https://doi.org/10.21147/j.issn.1000-9604.2024.02.04.
Google Scholar
Guillotin F, Fortier M, Portes M, Demattei C, Mousty E, Nouvellon E, et al. Vital NETosis vs. suicidal NETosis during normal pregnancy and preeclampsia. Front Cell Dev Biol. 2023;10:1099038. https://doi.org/10.3389/fcell.2022.1099038.
Google Scholar
Zhu D, Lu Y, Yang S, Hu T, Tan C, Liang R, et al. PAD4 inhibitor-functionalized layered double hydroxide nanosheets for synergistic sonodynamic therapy/immunotherapy of tumor metastasis. Adv Sci. 2024;11(26):e2401064. https://doi.org/10.1002/advs.202401064.
Google Scholar
Moiana M, Aranda F, de Larrañaga G. A focus on the roles of histones in health and diseases. Clin Biochem. 2021;94:12–9. https://doi.org/10.1016/j.clinbiochem.2021.04.019.
Google Scholar
Xie W, Yu X, Yang Q, Ke N, Wang P, Kong H, Wu X, Ma P, Chen L, Yang J, Feng X, Wang Y, Shi H, Chen L, Liu YH, Ding BS, Wei Q, Jiang H. An immunomechanical checkpoint PYK2 governs monocyte-to-macrophage differentiation in pancreatic cancer. Cancer Discov. 2025. https://doi.org/10.1158/2159-8290.CD-24-1712. Epub ahead of print. PMID: 40338055.
Yang C, Wang Z, Li L, Zhang Z, Jin X, Wu P, et al. Aged neutrophils form mitochondria-dependent vital NETs to promote breast cancer lung metastasis. J Immunother Cancer. 2021;9(10):e002875. https://doi.org/10.1136/jitc-2021-002875.
Google Scholar
Hao X, Gu H, Chen C, Huang D, Zhao Y, Xie L, Zou Y, Shu HS, Zhang Y, He X, Lai X, Zhang X, Zhou BO, Zhang CC, Chen GQ, Yu Z, Yang Y, Zheng J. Metabolic imaging reveals a unique preference of symmetric cell division and homing of Leukemia-Initiating cells in an endosteal niche. Cell Metab. 2019;29(4):950–e9656. Epub 2018 Dec 20. PMID: 30581117.
Google Scholar
Wu Q, Hu G. A genetic portrait of metastatic seeds in lung adenocarcinoma. Cancer Cell. 2023;41(5):828–30. https://doi.org/10.1016/j.ccell.2023.04.004.
Google Scholar
West AP, Khoury-Hanold W, Staron M, Tal MC, Pineda CM, Lang SM, et al. Mitochondrial DNA stress primes the antiviral innate immune response. Nature. 2015;520(7548):553–7. https://doi.org/10.1038/nature14156.
Google Scholar
Yamazaki T, Kirchmair A, Sato A, Buqué A, Rybstein M, Petroni G, Bloy N, Finotello F, Stafford L, Navarro Manzano E, de la Ayala F, García-Martínez E, Formenti SC, Trajanoski Z, Galluzzi L. Mitochondrial DNA drives abscopal responses to radiation that are inhibited by autophagy. Nat Immunol. 2020;21(10):1160–71. https://doi.org/10.1038/s41590-020-0751-0. Epub 2020 Aug 3. PMID: 32747819.
Google Scholar
Ahn J, Xia T, Konno H, Konno K, Ruiz P, Barber GN. Inflammation-driven carcinogenesis is mediated through STING. Nat Commun. 2014;5(1):5166. https://doi.org/10.1038/ncomms6166.
Google Scholar
Bakhoum SF, Ngo B, Laughney AM, Cavallo JA, Murphy CJ, Ly P, et al. Chromosomal instability drives metastasis through a cytosolic DNA response. Nature. 2018;553(7689):467–72. https://doi.org/10.1038/nature25432.
Google Scholar
Cheng AN, Cheng LC, Kuo CL, Lo YK, Chou HY, Chen CH, et al. Mitochondrial lon-induced mtDNA leakage contributes to PD-L1-mediated immunoescape via STING-IFN signaling and extracellular vesicles. J Immunother Cancer. 2020;8(2):e001372. https://doi.org/10.1136/jitc-2020-001372.
Google Scholar
Xiong S, Dong L, Cheng L. Neutrophils in cancer carcinogenesis and metastasis. J Hematol Oncol. 2021;14(1):173. https://doi.org/10.1186/s13045-021-01187-y.
Google Scholar
Yang LY, Luo Q, Lu L, Zhu WW, Sun HT, Wei R, Lin ZF, Wang XY, Wang CQ, Lu M, Jia HL, Chen JH, Zhang JB, Qin LX. Increased neutrophil extracellular traps promote metastasis potential of hepatocellular carcinoma via provoking tumorous inflammatory response. J Hematol Oncol. 2020;13(1):3. https://doi.org/10.1186/s13045-019-0836-0. PMID: 31907001; PMCID: PMC6945602.
Google Scholar
Demers M, Krause DS, Schatzberg D, Martinod K, Voorhees JR, Fuchs TA, et al. Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancer-associated thrombosis. Proc Natl Acad Sci U S A. 2012;109(32):13076–81. https://doi.org/10.1073/pnas.1200419109.
Google Scholar
Tohme S, Yazdani HO, Al-Khafaji AB, Chidi AP, Loughran P, Mowen K, et al. Neutrophil extracellular traps promote the development and progression of liver metastases after surgical stress. Cancer Res. 2016;76(6):1367–80. https://doi.org/10.1158/0008-5472.CAN-15-1591.
Google Scholar
Antonio N, Bønnelykke-Behrndtz ML, Ward LC, Collin J, Christensen IJ, Steiniche T, et al. The wound inflammatory response exacerbates growth of pre-neoplastic cells and progression to cancer. EMBO J. 2015;34(17):2219–36. https://doi.org/10.15252/embj.201490147.
Google Scholar
Hedrick CC, Malanchi I. Neutrophils in cancer: heterogeneous and multifaceted. Nat Rev Immunol. 2022;22(3):173–87. https://doi.org/10.1038/s41577-021-00571-6.
Google Scholar
Liu S, Wu W, Du Y, Yin H, Chen Q, Yu W, et al. The evolution and heterogeneity of neutrophils in cancers: origins, subsets, functions, orchestrations and clinical applications. Mol Cancer. 2023;22(1):148. https://doi.org/10.1186/s12943-023-01843-6.
Google Scholar
Butin-Israeli V, Bui TM, Wiesolek HL, Mascarenhas L, Lee JJ, Mehl LC, Knutson KR, Adam SA, Goldman RD, Beyder A, Wiesmuller L, Hanauer SB, Sumagin R. Neutrophil-induced genomic instability impedes resolution of inflammation and wound healing. J Clin Invest. 2019;129(2):712–26. Epub 2019 Jan 14. PMID: 30640176; PMCID: PMC6355304.
Google Scholar
Hsu YL, Hung JY, Chang WA, Lin YS, Pan YC, Tsai PH, et al. Hypoxic lung cancer-secreted exosomal miR-23a increased angiogenesis and vascular permeability by targeting prolyl hydroxylase and tight junction protein ZO-1. Oncogene. 2017;36(34):4929–42. https://doi.org/10.1038/onc.2017.105.
Google Scholar
Shang M, Weng L, Wu S, Liu B, Yin X, Wang Z, Mao A. HP1BP3 promotes tumor growth and metastasis by upregulating miR-23a to target TRAF5 in esophageal squamous cell carcinoma. Am J Cancer Res. 2021;11(6):2928–43. PMID: 34249436; PMCID: PMC8263663.
Zhou X, Yan T, Huang C, Xu Z, Wang L, Jiang E, Wang H, Chen Y, Liu K, Shao Z, Shang Z. Melanoma cell-secreted Exosomal miR-155-5p induce proangiogenic switch of cancer-associated fibroblasts via SOCS1/JAK2/STAT3 signaling pathway. J Exp Clin Cancer Res. 2018;37(1):242. https://doi.org/10.1186/s13046-018-0911-3. PMID: 30285793; PMCID: PMC6169013.
Google Scholar
Zheng Z, Sun R, Zhao HJ, Fu D, Zhong HJ, Weng XQ, et al. MiR155 sensitized B-lymphoma cells to anti-PD-L1 antibody via PD-1/PD-L1-mediated lymphoma cell interaction with CD8 + T cells. Mol Cancer. 2019;18(1):54. https://doi.org/10.1186/s12943-019-0977-3.
Google Scholar
Carmody RN, Sarkar A, Reese AT. Gut microbiota through an evolutionary lens. Science. 2021;372(6541):462–3. https://doi.org/10.1126/science.abf0590.
Google Scholar
Ternes D, Tsenkova M, Pozdeev VI, Meyers M, Koncina E, Atatri S, et al. The gut microbial metabolite formate exacerbates colorectal cancer progression. Nat Metab. 2022;4(4):458–75. https://doi.org/10.1038/s42255-022-00558-0.
Google Scholar
Saitoh T, Komano J, Saitoh Y, Misawa T, Takahama M, Kozaki T, et al. Neutrophil extracellular traps mediate a host defense response to human immunodeficiency virus-1. Cell Host Microbe. 2012;12(1):109–16. https://doi.org/10.1016/j.chom.2012.05.015.
Google Scholar
Ouyang D, Xiang T, Chen Y, Song M, Zhao J, Chen H, Li S, Zhang L, Xu C, Ren Y, Tao Y, Wang Q, He J, Li Y, Xie S, Liu Y, Wang Y, Yang X, You J, Xie S, Li Y, Weng D, Pan Q, Yang Q, Xia J. The CXCL10-CXCR3 axis induces Tumor-Associated neutrophils to interfere with CTLs-Mediated antitumor activity in EBV-Associated epithelial Cancers. Adv sci (Weinh). 2025;e00950. https://doi.org/10.1002/advs.202500950. Epub ahead of print. PMID: 40686457.
Deng Z, Mei S, Ouyang Z, Wang R, Wang L, Zou B, Dai J, Mao K, Li Q, Guo Q, Yi C, Meng F, Xie M, Zhang X, Wang R, Deng T, Wang Z, Li X, Wang Q, Liu B, Tian X. Dysregulation of gut microbiota stimulates NETs-driven HCC intrahepatic metastasis: therapeutic implications of healthy faecal microbiota transplantation. Gut Microbes. 2025;17(1):2476561. Epub 2025 Mar 18. PMID: 40099491; PMCID: PMC11925110.
Google Scholar
Fu A, Yao B, Dong T, Chen Y, Yao J, Liu Y, Li H, Bai H, Liu X, Zhang Y, Wang C, Guo Y, Li N, Cai S. Tumor-resident intracellular microbiota promotes metastatic colonization in breast cancer. Cell. 2022;185(8):1356–e137226. https://doi.org/10.1016/j.cell.2022.02.027. Epub 2022 Apr 7. PMID: 35395179.
Google Scholar
Jin C, Lagoudas GK, Zhao C, Bullman S, Bhutkar A, Hu B, Ameh S, Sandel D, Liang XS, Mazzilli S, Whary MT, Meyerson M, Germain R, Blainey PC, Fox JG, Jacks T. Commensal microbiota promote lung cancer development via γδ T cells. Cell. 2019;176(5):998–e101316. Epub 2019 Jan 31. PMID: 30712876; PMCID: PMC6691977.
Google Scholar
Branzk N, Papayannopoulos V. Molecular mechanisms regulating NETosis in infection and disease. Semin Immunopathol. 2013;35(4):513–30. https://doi.org/10.1007/s00281-013-0384-6.
Google Scholar
Liu C, Qi J, Shan B, Gao R, Gao F, Xie H, et al. Pretreatment with cathelicidin-BF ameliorates Pseudomonas aeruginosa pneumonia in mice by enhancing NETosis and the autophagy of recruited neutrophils and macrophages. Int Immunopharmacol. 2018;65:382–91. https://doi.org/10.1016/j.intimp.2018.10.030.
Google Scholar
Garley M, Jabłońska E, Dąbrowska D. NETs in cancer. Tumour Biol. 2016;37(11):14355–61. https://doi.org/10.1007/s13277-016-5328-z.
Google Scholar
Xiao Y, Cong M, Li J, He D, Wu Q, Tian P, Wang Y, Yang S, Liang C, Liang Y, Wen J, Liu Y, Luo W, Lv X, He Y, Cheng DD, Zhou T, Zhao W, Zhang P, Zhang X, Xiao Y, Qian Y, Wang H, Gao Q, Yang QC, Yang Q, Hu G. Cathepsin C promotes breast cancer lung metastasis by modulating neutrophil infiltration and neutrophil extracellular trap formation. Cancer Cell. 2021;39(3):423–e4377. https://doi.org/10.1016/j.ccell.2020.12.012. Epub 2021 Jan 14. PMID: 33450198.
Google Scholar
Qi JL, He JR, Liu CB, Jin SM, Gao RY, Yang X, et al. Pulmonary Staphylococcus aureus infection regulates breast cancer cell metastasis via neutrophil extracellular traps (NETs) formation. MedComm. 2020;1(2):188–201. https://doi.org/10.1002/mco2.22.
Google Scholar
Munir H, Jones JO, Janowitz T, Hoffmann M, Euler M, Martins CP, et al. Stromal-driven and amyloid β-dependent induction of neutrophil extracellular traps modulates tumor growth. Nat Commun. 2021;12(1):683. https://doi.org/10.1038/s41467-021-20982-2.
Google Scholar
Xie M, Lin Z, Ji X, Luo X, Zhang Z, Sun M, et al. FGF19/FGFR4-mediated elevation of ETV4 facilitates hepatocellular carcinoma metastasis by upregulating PD-L1 and CCL2. J Hepatol. 2023;79(1):109–25. https://doi.org/10.1016/j.jhep.2023.02.036.
Google Scholar
Kim YC, Seok S, Zhang Y, Ma J, Kong B, Guo G, et al. Intestinal FGF15/19 physiologically repress hepatic lipogenesis in the late fed-state by activating SHP and DNMT3A. Nat Commun. 2020;11(1):5969. https://doi.org/10.1038/s41467-020-19803-9.
Google Scholar
Li C, Chen T, Liu J, Wang Y, Zhang C, Guo L, et al. FGF19-induced inflammatory CAF promoted neutrophil extracellular trap formation in the liver metastasis of colorectal cancer. Adv Sci. 2023;10(24):e2302613. https://doi.org/10.1002/advs.202302613.
Google Scholar
Cheng Y, Li H, Deng Y, Tai Y, Zeng K, Zhang Y, et al. Cancer-associated fibroblasts induce PDL1 + neutrophils through the IL6-STAT3 pathway that foster immune suppression in hepatocellular carcinoma. Cell Death Dis. 2018;9(4):422. https://doi.org/10.1038/s41419-018-0458-4.
Google Scholar
Takesue S, Ohuchida K, Shinkawa T, Otsubo Y, Matsumoto S, Sagara A, Yonenaga A, Ando Y, Kibe S, Nakayama H, Iwamoto C, Shindo K, Moriyama T, Nakata K, Miyasaka Y, Ohtsuka T, Toma H, Tominaga Y, Mizumoto K, Hashizume M, Nakamura M. Neutrophil extracellular traps promote liver micrometastasis in pancreatic ductal adenocarcinoma via the activation of cancer–associated fibroblasts. Int J Oncol. 2020;56(2):596–605. https://doi.org/10.3892/ijo.2019.4951. Epub 2019 Dec 24. PMID: 31894273.
Google Scholar
Chen J, Huang Z, Chen Y, Tian H, Chai P, Shen Y, et al. Lactate and lactylation in cancer. Signal Transduct Target Ther. 2025;10(1):38. https://doi.org/10.1038/s41392-024-02082-x.
Google Scholar
Wise AD, TenBarge EG, Mendonça JDC, Mennen EC, McDaniel SR, Reber CP, Holder BE, Bunch ML, Belevska E, Marshall MG, Vaccaro NM, Blakely CR, Wellawa DH, Ferris J, Sheldon JR, Bieber JD, Johnson JG, Burcham LR, Monteith AJ. Mitochondria sense bacterial lactate and drive release of neutrophil extracellular traps. Cell Host Microbe. 2025;33(3):341–e3579. Epub 2025 Feb 27. PMID: 40020664; PMCID: PMC11955204.
Google Scholar
Cao S, Liu P, Zhu H, Gong H, Yao J, Sun Y, et al. Extracellular acidification acts as a key modulator of neutrophil apoptosis and functions. PLoS One. 2015;10(9):e0139500. https://doi.org/10.1371/journal.pone.0139500.
Google Scholar
Trevani AS, Andonegui G, Giordano M, López DH, Gamberale R, Minucci F, Geffner JR. Extracellular acidification induces human neutrophil activation. J Immunol. 1999;162(8):4849–57 PMID: 10202029.
Google Scholar
Díaz FE, Dantas E, Cabrera M, Benítez CA, Delpino MV, Duette G, et al. Fever-range hyperthermia improves the anti-apoptotic effect induced by low pH on human neutrophils promoting a proangiogenic profile. Cell Death Dis. 2016;7(10):e2437. https://doi.org/10.1038/cddis.2016.337.
Google Scholar
Ashby BS. pH studies in human malignant tumours. Lancet. 1966;2(7458):312–5. https://doi.org/10.1016/s0140-6736(66)92598-0.
Google Scholar
Tannock IF, Rotin D. Acid pH in tumors and its potential for therapeutic exploitation. Cancer Res. 1989;49(16):4373–84. PMID: 2545340.
Google Scholar
Estrella V, Chen T, Lloyd M, Wojtkowiak J, Cornnell HH, Ibrahim-Hashim A, Bailey K, Balagurunathan Y, Rothberg JM, Sloane BF, Johnson J, Gatenby RA, Gillies RJ. Acidity generated by the tumor microenvironment drives local invasion. Cancer Res. 2013;73(5):1524–35. https://doi.org/10.1158/0008-5472.CAN-12-2796. Epub 2013 Jan 3. PMID: 23288510; PMCID: PMC3594450.
Google Scholar
Waldman AD, Fritz JM, Lenardo MJ. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat Rev Immunol. 2020;20(11):651–68. https://doi.org/10.1038/s41577-020-0306-5. Epub 2020 May 20. PMID: 32433532; PMCID: PMC7238960.
Google Scholar
Ramezani-Ali Akbari K, Khaki-Bakhtiarvand V, Mahmoudian J, Asgarian-Omran H, Shokri F, Hojjat-Farsangi M, Jeddi-Tehrani M, Shabani M. Cloning, expression and characterization of a peptibody to deplete myeloid derived suppressor cells in a murine mammary carcinoma model. Protein Expr Purif. 2022;200:106153. https://doi.org/10.1016/j.pep.2022.106153. Epub 2022 Aug 19. PMID: 35995320.
Google Scholar
Qin H, Lerman B, Sakamaki I, Wei G, Cha SC, Rao SS, Qian J, Hailemichael Y, Nurieva R, Dwyer KC, Roth J, Yi Q, Overwijk WW, Kwak LW. Generation of a new therapeutic peptide that depletes myeloid-derived suppressor cells in tumor-bearing mice. Nat Med. 2014;20(6):676–81. https://doi.org/10.1038/nm.3560. Epub 2014 May 25. PMID: 24859530; PMCID: PMC4048321.
Google Scholar
Tessier-Cloutier B, Twa DD, Marzban M, Kalina J, Chun HE, Pavey N, Tanweer Z, Katz RL, Lum JJ, Salina D. The presence of tumour-infiltrating neutrophils is an independent adverse prognostic feature in clear cell renal cell carcinoma. J Pathol Clin Res. 2021;7(4):385–96. Epub 2021 Mar 4. PMID: 33665979; PMCID: PMC8185362.
Google Scholar
Xia X, Zhang Z, Zhu C, Ni B, Wang S, Yang S, Yu F, Zhao E, Li Q, Zhao G. Neutrophil extracellular traps promote metastasis in gastric cancer patients with postoperative abdominal infectious complications. Nat Commun. 2022;13(1):1017. https://doi.org/10.1038/s41467-022-28492-5. PMID: 35197446; PMCID: PMC8866499.
Google Scholar
Guo M, Sheng W, Yuan X, Wang X. Neutrophils as promising therapeutic targets in pancreatic cancer liver metastasis. Int Immunopharmacol. 2024;140:112888. https://doi.org/10.1016/j.intimp.2024.112888. Epub 2024 Aug 11. PMID: 39133956.
Google Scholar
Zhang Y, Guo L, Dai Q, Shang B, Xiao T, Di X, Zhang K, Feng L, Shou J, Wang Y. A signature for pan-cancer prognosis based on neutrophil extracellular traps. J Immunother Cancer. 2022;10(6):e004210. https://doi.org/10.1136/jitc-2021-004210. PMID: 35688556; PMCID: PMC9189842.
Google Scholar
Masucci MT, Minopoli M, Del Vecchio S, Carriero MV. The emerging role of neutrophil extracellular traps (NETs) in tumor progression and metastasis. Front Immunol. 2020;11:1749. https://doi.org/10.3389/fimmu.2020.01749. PMID: 33042107; PMCID: PMC7524869.
Google Scholar
Gerstberger S, Jiang Q, Ganesh K, Metastasis. Cell. 2023;186(8):1564–79. https://doi.org/10.1016/j.cell.2023.03.003. PMID: 37059065; PMCID: PMC10511214.
Google Scholar
Albrengues J, Shields MA, Ng D, Park CG, Ambrico A, Poindexter ME, Upadhyay P, Uyeminami DL, Pommier A, Küttner V, Bružas E, Maiorino L, Bautista C, Carmona EM, Gimotty PA, Fearon DT, Chang K, Lyons SK, Pinkerton KE, Trotman LC, Goldberg MS, Yeh JT, Egeblad M. Neutrophil extracellular traps produced during inflammation awaken dormant cancer cells in mice. Science. 2018;361(6409):eaao4227. https://doi.org/10.1126/science.aao4227. PMID: 30262472; PMCID: PMC6777850.
Google Scholar
Fang Q, Stehr AM, Naschberger E, Knopf J, Herrmann M, Stürzl M. No NETs no TIME: crosstalk between neutrophil extracellular traps and the tumor immune microenvironment. Front Immunol. 2022;13:1075260. https://doi.org/10.3389/fimmu.2022.1075260. PMID: 36618417; PMCID: PMC9816414.
Google Scholar
Ganesan R, Bhasin SS, Bakhtiary M, Krishnan U, Cheemarla NR, Thomas BE, Bhasin MK, Sukhatme VP. Taxane chemotherapy induces stromal injury that leads to breast cancer dormancy escape. PLoS Biol. 2023;21(9):e3002275. https://doi.org/10.1371/journal.pbio.3002275. PMID: 37699010; PMCID: PMC10497165.
Google Scholar
Mousset A, Albrengues J. NETs unleashed: neutrophil extracellular traps boost chemotherapy against colorectal cancer. J Clin Invest. 2024;134(5):e178344. https://doi.org/10.1172/JCI178344. PMID: 38426501; PMCID: PMC10904039.
Google Scholar
Teijeira Á, Garasa S, Gato M, Alfaro C, Migueliz I, Cirella A, de Andrea C, Ochoa MC, Otano I, Etxeberria I, Andueza MP, Nieto CP, Resano L, Azpilikueta A, Allegretti M, de Pizzol M, Ponz-Sarvisé M, Rouzaut A, Sanmamed MF, Schalper K, Carleton M, Mellado M, Rodriguez-Ruiz ME, Berraondo P, Perez-Gracia JL, Melero I. CXCR1 and CXCR2 chemokine receptor agonists produced by tumors induce neutrophil extracellular traps that interfere with immune cytotoxicity. Immunity. 2020;52(5):856–e8718. https://doi.org/10.1016/j.immuni.2020.03.001. Epub 2020 Apr 13. PMID: 32289253.
Google Scholar
Taifour T, Attalla SS, Zuo D, Gu Y, Sanguin-Gendreau V, Proud H, Solymoss E, Bui T, Kuasne H, Papavasiliou V, Lee CG, Kamle S, Siegel PM, Elias JA, Park M, Muller WJ. The tumor-derived cytokine Chi3l1 induces neutrophil extracellular traps that promote T cell exclusion in triple-negative breast cancer. Immunity. 2023;56(12):2755–e27728. Epub 2023 Nov 30. PMID: 38039967.
Google Scholar
Yang L, Liu Q, Zhang X, Liu X, Zhou B, Chen J, Huang D, Li J, Li H, Chen F, Liu J, Xing Y, Chen X, Su S, Song E. DNA of neutrophil extracellular traps promotes cancer metastasis via CCDC25. Nature. 2020;583(7814):133–8. https://doi.org/10.1038/s41586-020-2394-6. Epub 2020 Jun 11. PMID: 32528174.
Google Scholar
Najmeh S, Cools-Lartigue J, Rayes RF, Gowing S, Vourtzoumis P, Bourdeau F, Giannias B, Berube J, Rousseau S, Ferri LE, Spicer JD. Neutrophil extracellular traps sequester circulating tumor cells via β1-integrin mediated interactions. Int J Cancer. 2017;140(10):2321–30. https://doi.org/10.1002/ijc.30635. Epub 2017 Mar 2. PMID: 28177522.
Cools-Lartigue J, Spicer J, McDonald B, Gowing S, Chow S, Giannias B, Bourdeau F, Kubes P, Ferri L. Neutrophil extracellular traps sequester Circulating tumor cells and promote metastasis. J Clin Invest. 2013;123(8):3446–58. Epub ahead of print. PMID: 23863628; PMCID: PMC3726160.
Google Scholar
Hu C, Long L, Lou J, Leng M, Yang Q, Xu X, Zhou X. CTC-neutrophil interaction: A key driver and therapeutic target of cancer metastasis. Biomed Pharmacother. 2024;180:117474. https://doi.org/10.1016/j.biopha.2024.117474. Epub 2024 Sep 23. PMID: 39316968.
Peinado H, Zhang H, Matei IR, Costa-Silva B, Hoshino A, Rodrigues G, Psaila B, Kaplan RN, Bromberg JF, Kang Y, Bissell MJ, Cox TR, Giaccia AJ, Erler JT, Hiratsuka S, Ghajar CM, Lyden D. Pre-metastatic niches: organ-specific homes for metastases. Nat Rev Cancer. 2017;17(5):302–17. https://doi.org/10.1038/nrc.2017.6. Epub 2017 Mar 17. PMID: 28303905.
Jia J, Wang Y, Li M, Wang F, Peng Y, Hu J, Li Z, Bian Z, Yang S. Neutrophils in the premetastatic niche: key functions and therapeutic directions. Mol Cancer. 2024;23(1):200. https://doi.org/10.1186/s12943-024-02107-7. PMID: 39277750; PMCID: PMC11401288.
Google Scholar
Lee W, Ko SY, Mohamed MS, Kenny HA, Lengyel E, Naora H. Neutrophils facilitate ovarian cancer premetastatic niche formation in the omentum. J Exp Med. 2019;216(1):176–94. https://doi.org/10.1084/jem.20181170. Epub 2018 Dec 19. PMID: 30567719; PMCID: PMC6314534.
Google Scholar
Lee W, Naora H. Neutrophils fertilize the pre-metastatic niche. Aging (Albany NY). 2019;11(17):6624–5. https://doi.org/10.18632/aging.102258. Epub 2019 Sep 10. PMID: 31509520. PMCID: PMC6756893.
Google Scholar
Perego M, Tyurin VA, Tyurina YY, Yellets J, Nacarelli T, Lin C, Nefedova Y, Kossenkov A, Liu Q, Sreedhar S, Pass H, Roth J, Vogl T, Feldser D, Zhang R, Kagan VE, Gabrilovich DI. Reactivation of dormant tumor cells by modified lipids derived from stress-activated neutrophils. Sci Transl Med. 2020;12(572):eabb5817. https://doi.org/10.1126/scitranslmed.abb5817. PMID: 33268511; PMCID: PMC8085740.
Google Scholar
Wculek SK, Malanchi I. Neutrophils support lung colonization of metastasis-initiating breast cancer cells. Nature. 2015;528(7582):413–7. https://doi.org/10.1038/nature16140 Epub 2015 Dec 9. Erratum in: Nature. 2019;571(7763):E2. https://doi.org/10.1038/s41586-019-1328-7 . PMID: 26649828; PMCID: PMC4700594. .
Google Scholar
Liu Y, Gu Y, Han Y, Zhang Q, Jiang Z, Zhang X, Huang B, Xu X, Zheng J, Cao X. Tumor Exosomal RNAs Promote Lung Pre-metastatic Niche Formation by Activating Alveolar Epithelial TLR3 to Recruit Neutrophils. Cancer Cell. 2016;30(2):243–56. https://doi.org/10.1016/j.ccell.2016.06.021. PMID: 27505671.
Bellomo G, Rainer C, Quaranta V, Astuti Y, Raymant M, Boyd E, Stafferton R, Campbell F, Ghaneh P, Halloran CM, Hammond DE, Morton JP, Palmer D, Vimalachandran D, Jones R, Mielgo A, Schmid MC. Chemotherapy-induced infiltration of neutrophils promotes pancreatic cancer metastasis via Gas6/AXL signalling axis. Gut. 2022;71(11):2284–99. https://doi.org/10.1136/gutjnl-2021-325272. Epub 2022 Jan 12. PMID: 35022267; PMCID: PMC9554050.
Google Scholar
Rys RN, Calcinotto A. Senescent neutrophils: a hidden role in cancer progression. Trends Cell Biol. 2024;S0962–8924(24):00187–9. https://doi.org/10.1016/j.tcb.2024.09.001. Epub ahead of print. PMID: 39362804.
Google Scholar
Tyagi A, Sharma S, Wu K, Wu SY, Xing F, Liu Y, Zhao D, Deshpande RP, D’Agostino RB Jr, Watabe K. Nicotine promotes breast cancer metastasis by stimulating N2 neutrophils and generating pre-metastatic niche in lung. Nat Commun. 2021;12(1):474. https://doi.org/10.1038/s41467-020-20733-9. PMID: 33473115; PMCID: PMC7817836.
Google Scholar
Wieland E, Rodriguez-Vita J, Liebler SS, Mogler C, Moll I, Herberich SE, Espinet E, Herpel E, Menuchin A, Chang-Claude J, Hoffmeister M, Gebhardt C, Brenner H, Trumpp A, Siebel CW, Hecker M, Utikal J, Sprinzak D, Fischer A. Endothelial Notch1 activity facilitates metastasis. Cancer Cell. 2017;31(3):355–67. Epub 2017 Feb 23. PMID: 28238683.
Google Scholar
Fang JH, Zhang ZJ, Shang LR, Luo YW, Lin YF, Yuan Y, Zhuang SM. Hepatoma cell-secreted Exosomal microRNA-103 increases vascular permeability and promotes metastasis by targeting junction proteins. Hepatology. 2018;68(4):1459–75. https://doi.org/10.1002/hep.29920. Epub 2018 Jul 25. PMID: 29637568.
Google Scholar
Kuang DM, Zhao Q, Wu Y, Peng C, Wang J, Xu Z, Yin XY, Zheng L. Peritumoral neutrophils link inflammatory response to disease progression by fostering angiogenesis in hepatocellular carcinoma. J Hepatol. 2011;54(5):948–55. Epub 2010 Nov 13. PMID: 21145847.
Google Scholar
Kuang DM, Peng C, Zhao Q, Wu Y, Zhu LY, Wang J, Yin XY, Li L, Zheng L. Tumor-activated monocytes promote expansion of IL-17-producing CD8 + T cells in hepatocellular carcinoma patients. J Immunol. 2010;185(3):1544–9. https://doi.org/10.4049/jimmunol.0904094. Epub 2010 Jun 25. PMID: 20581151.
Google Scholar
Jiang ZZ, Peng ZP, Liu XC, Guo HF, Zhou MM, Jiang D, Ning WR, Huang YF, Zheng L, Wu Y. Neutrophil extracellular traps induce tumor metastasis through dual effects on cancer and endothelial cells. Oncoimmunology. 2022;11(1):2052418. PMID: 35309732; PMCID: PMC8928819.
Google Scholar
Lu K, Xia Y, Cheng P, Li Y, He L, Tao L, Wei Z, Lu Y. Synergistic potentiation of the anti-metastatic effect of a Ginseng-Salvia miltiorrhiza herbal pair and its biological ingredients via the suppression of CD62E-dependent neutrophil infiltration and NETformation. J Adv Res. 2024;S2090–1232(24)00490-9. https://doi.org/10.1016/j.jare.2024.10.036. Epub ahead of print. PMID: 39481643.
Martins-Cardoso K, Almeida VH, Bagri KM, Rossi MID, Mermelstein CS, König S, Monteiro RQ. Neutrophil extracellular traps (NETs) promote Pro-Metastatic phenotype in human breast cancer cells through Epithelial-Mesenchymal transition. Cancers (Basel). 2020;12(6):1542. https://doi.org/10.3390/cancers12061542. PMID: 32545405; PMCID: PMC7352979.
Google Scholar
Kajioka H, Kagawa S, Ito A, Yoshimoto M, Sakamoto S, Kikuchi S, Kuroda S, Yoshida R, Umeda Y, Noma K, Tazawa H, Fujiwara T. Targeting neutrophil extracellular traps with thrombomodulin prevents pancreatic cancer metastasis. Cancer Lett. 2021;497:1–13. Epub 2020 Oct 13. PMID: 33065249.
Google Scholar
Weide LM, Schedel F, Weishaupt C. Neutrophil extracellular traps correlate with tumor necrosis and size in human malignant melanoma metastases. Biology (Basel). 2023;12(6):822. https://doi.org/10.3390/biology12060822. PMID: 37372107; PMCID: PMC10295294.
Google Scholar
Yee PP, Wei Y, Kim SY, Lu T, Chih SY, Lawson C, Tang M, Liu Z, Anderson B, Thamburaj K, Young MM, Aregawi DG, Glantz MJ, Zacharia BE, Specht CS, Wang HG, Li W. Neutrophil-induced ferroptosis promotes tumor necrosis in glioblastoma progression. Nat Commun. 2020;11(1):5424. https://doi.org/10.1038/s41467-020-19193-y. PMID: 33110073; PMCID: PMC7591536.
Google Scholar
Chen F, Tang H, Cai X, Lin J, Kang R, Tang D, Liu J. DAMPs in Immunosenescence and cancer. Semin Cancer Biol. 2024;106–107:123–42. Epub ahead of print. PMID: 39349230.
Google Scholar
Tang D, Kang R, Zeh HJ, Lotze MT. The multifunctional protein HMGB1: 50 years of discovery. Nat Rev Immunol. 2023;23(12):824–41. https://doi.org/10.1038/s41577-023-00894-6. Epub 2023 Jun 15. PMID: 37322174.
Google Scholar
Liu Y, Yan W, Tohme S, Chen M, Fu Y, Tian D, Lotze M, Tang D, Tsung A. Hypoxia induced HMGB1 and mitochondrial DNA interactions mediate tumor growth in hepatocellular carcinoma through Toll-like receptor 9. J Hepatol. 2015;63(1):114–21. Epub 2015 Feb 12. PMID: 25681553; PMCID: PMC4475488.
Google Scholar
Yang Y, Yang J, Li L, Shao Y, Liu L, Sun B. Neutrophil chemotaxis score and chemotaxis-related genes have the potential for clinical application to prognosticate the survival of patients with tumours. BMC Cancer. 2024;24(1):1244. https://doi.org/10.1186/s12885-024-12993-1. PMID: 39379856; PMCID: PMC11463147.
Google Scholar
Kamphorst AO, Wieland A, Nasti T, Yang S, Zhang R, Barber DL, Konieczny BT, Daugherty CZ, Koenig L, Yu K, Sica GL, Sharpe AH, Freeman GJ, Blazar BR, Turka LA, Owonikoko TK, Pillai RN, Ramalingam SS, Araki K, Ahmed R. Rescue of exhausted CD8 T cells by PD-1-targeted therapies is CD28-dependent. Science. 2017;355(6332):1423–7. https://doi.org/10.1126/science.aaf0683. Epub 2017 Mar 9. PMID: 28280249; PMCID: PMC5595217.
Google Scholar
ten Hoeve J, Morris C, Heisterkamp N, Groffen J. Isolation and chromosomal localization of CRKL, a human crk-like gene. Oncogene. 1993;8(9):2469–74. PMID: 8361759.
Google Scholar
Zhang J, Gao X, Schmit F, Adelmant G, Eck MJ, Marto JA, Zhao JJ, Roberts TM. CRKL mediates p110β-Dependent PI3K signaling in PTEN-Deficient cancer cells. Cell Rep. 2017;20(3):549–57. PMID: 28723560; PMCID: PMC5704918.
Google Scholar
Sattler M, Salgia R. Role of the adapter protein CRKL in signal transduction of normal hematopoietic and BCR/ABL-transformed cells. Leukemia. 1998;12(5):637–44. https://doi.org/10.1038/sj.leu.2401010. PMID: 9593259.
Xie P, Yu M, Zhang B, Yu Q, Zhao Y, Wu M, Jin L, Yan J, Zhou B, Liu S, Li X, Zhou C, Zhu X, Huang C, Xu Y, Xiao Y, Zhou J, Fan J, Hung MC, Ye Q, Guo L, Li H. CRKL dictates anti-PD-1 resistance by mediating tumor-associated neutrophil infiltration in hepatocellular carcinoma. J Hepatol. 2024;81(1):93–107. https://doi.org/10.1016/j.jhep.2024.02.009. Epub 2024 Feb 23. PMID: 38403027.
Google Scholar
Lee YH, Martin-Orozco N, Zheng P, Li J, Zhang P, Tan H, Park HJ, Jeong M, Chang SH, Kim BS, Xiong W, Zang W, Guo L, Liu Y, Dong ZJ, Overwijk WW, Hwu P, Yi Q, Kwak L, Yang Z, Mak TW, Li W, Radvanyi LG, Ni L, Liu D, Dong C. Inhibition of the B7-H3 immune checkpoint limits tumor growth by enhancing cytotoxic lymphocyte function. Cell Res. 2017;27(8):1034–45. https://doi.org/10.1038/cr.2017.90. Epub 2017 Jul 7. PMID: 28685773; PMCID: PMC5539354.
Google Scholar
Suh WK, Gajewska BU, Okada H, Gronski MA, Bertram EM, Dawicki W, Duncan GS, Bukczynski J, Plyte S, Elia A, Wakeham A, Itie A, Chung S, Da Costa J, Arya S, Horan T, Campbell P, Gaida K, Ohashi PS, Watts TH, Yoshinaga SK, Bray MR, Jordana M, Mak TW. The B7 family member B7-H3 preferentially down-regulates T helper type 1-mediated immune responses. Nat Immunol. 2003;4(9):899–906. https://doi.org/10.1038/ni967. Epub 2003 Aug 17. PMID: 12925852.
Google Scholar
Xiong G, Chen Z, Liu Q, Peng F, Zhang C, Cheng M, Ling R, Chen S, Liang Y, Chen D, Zhou Q. CD276 regulates the immune escape of esophageal squamous cell carcinoma through CXCL1-CXCR2 induced NETs. J Immunother Cancer. 2024;12(5):e008662. https://doi.org/10.1136/jitc-2023-008662. PMID: 38724465; PMCID: PMC11086492.
Google Scholar
Song M, Zhang C, Cheng S, Ouyang D, Ping Y, Yang J, Zhang Y, Tang Y, Chen H, Wang QJ, Li YQ, He J, Xiang T, Zhang Y, Xia JC. DNA of Neutrophil Extracellular Traps Binds TMCO6 to Impair CD8 + T-cell Immunity in Hepatocellular Carcinoma. Cancer Res. 2024;84(10):1613–29. https://doi.org/10.1158/0008-5472.CAN-23-2986. PMID: 38381538.
Teijeira A, Garasa S, Ochoa MC, Villalba M, Olivera I, Cirella A, Eguren-Santamaria I, Berraondo P, Schalper KA, de Andrea CE, Sanmamed MF, Melero I. IL8, Neutrophils, and NETs in a collusion against cancer immunity and immunotherapy. Clin Cancer Res. 2021;27(9):2383–93. https://doi.org/10.1158/1078-0432.CCR-20-1319. Epub 2020 Dec 29. PMID: 33376096.
Google Scholar
Zhu X, Heng Y, Ma J, Zhang D, Tang D, Ji Y, He C, Lin H, Ding X, Zhou J, Tao L, Lu L. Prolonged survival of neutrophils induced by Tumor-Derived G-CSF/GM-CSF promotes immunosuppression and progression in laryngeal squamous cell carcinoma. Adv Sci (Weinh). 2024;11(46):e2400836. https://doi.org/10.1002/advs.202400836. Epub 2024 Oct 24. PMID: 39447112; PMCID: PMC11633501.
Google Scholar
Meng Y, Ye F, Nie P, Zhao Q, An L, Wang W, Qu S, Shen Z, Cao Z, Zhang X, Jiao S, Wu D, Zhou Z, Wei L. Immunosuppressive CD10 + ALPL + neutrophils promote resistance to anti-PD-1 therapy in HCC by mediating irreversible exhaustion of T cells. J Hepatol. 2023;79(6):1435–49. Epub 2023 Sep 7. PMID: 37689322.
Google Scholar
Gungabeesoon J, Gort-Freitas NA, Kiss M, Bolli E, Messemaker M, Siwicki M, Hicham M, Bill R, Koch P, Cianciaruso C, Duval F, Pfirschke C, Mazzola M, Peters S, Homicsko K, Garris C, Weissleder R, Klein AM, Pittet MJ. A neutrophil response linked to tumor control in immunotherapy. Cell. 2023;186(7):1448–e146420. https://doi.org/10.1016/j.cell.2023.02.032. PMID: 37001504; PMCID: PMC10132778.
Google Scholar
Hirschhorn D, Budhu S, Kraehenbuehl L, Gigoux M, Schröder D, Chow A, Ricca JM, Gasmi B, De Henau O, Mangarin LMB, Li Y, Hamadene L, Flamar AL, Choi H, Cortez CA, Liu C, Holland A, Schad S, Schulze I, Betof Warner A, Hollmann TJ, Arora A, Panageas KS, Rizzuto GA, Duhen R, Weinberg AD, Spencer CN, Ng D, He XY, Albrengues J, Redmond D, Egeblad M, Wolchok JD, Merghoub T. T cell immunotherapies engage neutrophils to eliminate tumor antigen escape variants. Cell. 2023;186(7):1432–e144717. https://doi.org/10.1016/j.cell.2023.03.007. PMID: 37001503; PMCID: PMC10994488.
Google Scholar
Zeng W, Zhang R, Huang P, Chen M, Chen H, Zeng X, Liu J, Zhang J, Huang D, Lao L. Ferroptotic neutrophils induce immunosuppression and chemoresistance in breast cancer. Cancer Res. 2025;85(3):477–96. PMID: 39531510; PMCID: PMC11786957.
Google Scholar
Caronni N, La Terza F, Vittoria FM, Barbiera G, Mezzanzanica L, Cuzzola V, Barresi S, Pellegatta M, Canevazzi P, Dunsmore G, Leonardi C, Montaldo E, Lusito E, Dugnani E, Citro A, Ng MSF, Schiavo Lena M, Drago D, Andolfo A, Brugiapaglia S, Scagliotti A, Mortellaro A, Corbo V, Liu Z, Mondino A, Dellabona P, Piemonti L, Taveggia C, Doglioni C, Cappello P, Novelli F, Iannacone M, Ng LG, Ginhoux F, Crippa S, Falconi M, Bonini C, Naldini L, Genua M, Ostuni R. IL-1β + macrophages fuel pathogenic inflammation in pancreatic cancer. Nature. 2023;623(7986):415–22. https://doi.org/10.1038/s41586-023-06685-2. Epub 2023 Nov 1. PMID: 37914939.
Google Scholar
Kaler P, Augenlicht L, Klampfer L. Macrophage-derived IL-1beta stimulates Wnt signaling and growth of colon cancer cells: a crosstalk interrupted by vitamin D3. Oncogene. 2009;28(44):3892–902. https://doi.org/10.1038/onc.2009.247. Epub 2009 Aug 24. PMID: 19701245; PMCID: PMC2783659.
Google Scholar
Mousset A, Lecorgne E, Bourget I, Lopez P, Jenovai K, Cherfils-Vicini J, Dominici C, Rios G, Girard-Riboulleau C, Liu B, Spector DL, Ehmsen S, Renault S, Hego C, Mechta-Grigoriou F, Bidard FC, Terp MG, Egeblad M, Gaggioli C, Albrengues J. Neutrophil extracellular traps formed during chemotherapy confer treatment resistance via TGF-β activation. Cancer Cell. 2023;41(4):757–e77510. https://doi.org/10.1016/j.ccell.2023.03.008. PMID: 37037615; PMCID: PMC10228050.
Google Scholar
Nakazawa D, Kumar SV, Marschner J, Desai J, Holderied A, Rath L, Kraft F, Lei Y, Fukasawa Y, Moeckel GW, Angelotti ML, Liapis H, Anders HJ. Histones and neutrophil extracellular traps enhance tubular necrosis and remote organ injury in ischemic AKI. J Am Soc Nephrol. 2017;28(6):1753–68. Epub 2017 Jan 10. PMID: 28073931; PMCID: PMC5461800.
Google Scholar
Mousset A, Bellone L, Gaggioli C, Albrengues J. NETscape or nethance: tailoring anti-cancer therapy. Trends Cancer. 2024;10(7):655–67. https://doi.org/10.1016/j.trecan.2024.03.007. Epub 2024 Apr 24. PMID: 38664080.
Google Scholar
Teijeira A, Garasa S, Ochoa MC, Sanchez-Gregorio S, Gomis G, Luri-Rey C, Martinez-Monge R, Pinci B, Valencia K, Palencia B, Barbés B, Bolaños E, Azpilikueta A, García-Cardosa M, Burguete J, Eguren-Santamaría I, Garate-Soraluze E, Berraondo P, Perez-Gracia JL, de Andrea CE, Rodriguez-Ruiz ME, Melero I. Low-Dose ionizing γ-Radiation elicits the extrusion of neutrophil extracellular traps. Clin Cancer Res. 2024;30(18):4131–42. https://doi.org/10.1158/1078-0432.CCR-23-3860. PMID: 38630754; PMCID: PMC11393545.
Google Scholar
Takeshima T, Pop LM, Laine A, Iyengar P, Vitetta ES, Hannan R. Key role for neutrophils in radiation-induced antitumor immune responses: potentiation with G-CSF. Proc Natl Acad Sci U S A. 2016;113(40):11300–5. https://doi.org/10.1073/pnas.1613187113. Epub 2016 Sep 20. PMID: 27651484; PMCID: PMC5056034.
Google Scholar
Elvington M, Scheiber M, Yang X, Lyons K, Jacqmin D, Wadsworth C, Marshall D, Vanek K, Tomlinson S. Complement-dependent modulation of antitumor immunity following radiation therapy. Cell Rep. 2014;8(3):818–30. https://doi.org/10.1016/j.celrep.2014.06.051. Epub 2014 Jul 24. PMID: 25066124; PMCID: PMC4137409.
Google Scholar
Nolan E, Bridgeman VL, Ombrato L, Karoutas A, Rabas N, Sewnath CAN, Vasquez M, Rodrigues FS, Horswell S, Faull P, Carter R, Malanchi I. Radiation exposure elicits a neutrophil-driven response in healthy lung tissue that enhances metastatic colonization. Nat Cancer. 2022;3(2):173–87. https://doi.org/10.1038/s43018-022-00336-7 Epub 2022 Feb 24. Erratum in: Nat Cancer. 2022;3(4):519. https://doi.org/10.1038/s43018-022-00373-2. PMID: 35221334; PMCID: PMC7612918 .
Google Scholar
de Ruiz-Fernández B, Moreno H, Valencia K, Perurena N, Ruedas P, Walle T, Pezonaga-Torres A, Hinojosa J, Guruceaga E, Pineda-Lucena A, Abengózar-Muela M, Cochonneau D, Zandueta C, Martínez-Canarias S, Teijeira Á, Ajona D, Ortiz-Espinosa S, Morales X, de Ortiz C, Santisteban M, Ramos-García LI, Guembe L, Strnad V, Heymann D, Hervás-Stubbs S, Pío R, Rodríguez-Ruiz ME, de Andrea CE, Vicent S, Melero I, Lecanda F, Martínez-Monge R. Tumor ENPP1 (CD203a)/Haptoglobin axis exploits Myeloid-Derived suppressor cells to promote Post-Radiotherapy local recurrence in breast cancer. Cancer Discov. 2022;12(5):1356–77. https://doi.org/10.1158/2159-8290.CD-21-0932. PMID: 35191482; PMCID: PMC7612709.
Google Scholar
Xia X, Zhang Z, Zhu C, Ni B, Wang S, Yang S, Yu F, Zhao E, Li Q, Zhao G. Neutrophil extracellular traps promote metastasis in gastric cancer patients with postoperative abdominal infectious complications. Nat Commun. 2022;13(1):1017. https://doi.org/10.1038/s41467-022-28492-5. Erratum in: Nat Commun. 2025;16(1):2381. https://doi.org/10.1038/s41467-025-57805-7. PMID: 35197446; PMCID: PMC8866499.
Shinde-Jadhav S, Mansure JJ, Rayes RF, Marcq G, Ayoub M, Skowronski R, Kool R, Bourdeau F, Brimo F, Spicer J, Kassouf W. Role of neutrophil extracellular traps in radiation resistance of invasive bladder cancer. Nat Commun. 2021;12(1):2776. https://doi.org/10.1038/s41467-021-23086-z. PMID: 33986291; PMCID: PMC8119713.
Google Scholar
Metzler KD, Goosmann C, Lubojemska A, Zychlinsky A, Papayannopoulos V. A myeloperoxidase-containing complex regulates neutrophil elastase release and actin dynamics during NETosis. Cell Rep. 2014;8(3):883–96. https://doi.org/10.1016/j.celrep.2014.06.044. Epub 2014 Jul 24. PMID: 25066128; PMCID: PMC4471680.
Google Scholar
Kawabata K, Hagio T, Matsuoka S. The role of neutrophil elastase in acute lung injury. Eur J Pharmacol. 2002;451(1):1–10. https://doi.org/10.1016/s0014-2999(02)02182-9. PMID: 12223222.
Hunter MG, Druhan LJ, Massullo PR, Avalos BR. Proteolytic cleavage of granulocyte colony-stimulating factor and its receptor by neutrophil elastase induces growth inhibition and decreased cell surface expression of the granulocyte colony-stimulating factor receptor. Am J Hematol. 2003;74(3):149–55. https://doi.org/10.1002/ajh.10434. PMID: 14587040.
Valenzuela-Fernández A, Planchenault T, Baleux F, Staropoli I, Le-Barillec K, Leduc D, Delaunay T, Lazarini F, Virelizier JL, Chignard M, Pidard D, Arenzana-Seisdedos F. Leukocyte elastase negatively regulates stromal cell-derived factor-1 (SDF-1)/CXCR4 binding and functions by amino-terminal processing of SDF-1 and CXCR4. J Biol Chem. 2002;277(18):15677–89. https://doi.org/10.1074/jbc.M111388200. Epub 2002 Feb 26. PMID: 11867624.
Google Scholar
Shang Y, Jiang YX, Ding ZJ, Shen AL, Xu SP, Yuan SY, Yao SL. Valproic acid attenuates the multiple-organ dysfunction in a rat model of septic shock. Chin Med J (Engl). 2010;123(19):2682–7. PMID: 21034653.
Google Scholar
Aldabbous L, Abdul-Salam V, McKinnon T, Duluc L, Pepke-Zaba J, Southwood M, Ainscough AJ, Hadinnapola C, Wilkins MR, Toshner M, Wojciak-Stothard B. Neutrophil extracellular traps promote angiogenesis: evidence from vascular pathology in pulmonary hypertension. Arterioscler Thromb Vasc Biol. 2016;36(10):2078–87. https://doi.org/10.1161/ATVBAHA.116.307634. Epub 2016 Jul 28. PMID: 27470511.
Google Scholar
Houghton AM, Rzymkiewicz DM, Ji H, Gregory AD, Egea EE, Metz HE, Stolz DB, Land SR, Marconcini LA, Kliment CR, Jenkins KM, Beaulieu KA, Mouded M, Frank SJ, Wong KK, Shapiro SD. Neutrophil elastase-mediated degradation of IRS-1 accelerates lung tumor growth. Nat Med. 2010;16(2):219–23. Epub 2010 Jan 17. PMID: 20081861; PMCID: PMC2821801.
Google Scholar
Caruso JA, Akli S, Pageon L, Hunt KK, Keyomarsi K. The Serine protease inhibitor Elafin maintains normal growth control by opposing the mitogenic effects of neutrophil elastase. Oncogene. 2015;34(27):3556–67. https://doi.org/10.1038/onc.2014.284. Epub 2014 Sep 8. PMID: 25195861; PMCID: PMC4362782.
Google Scholar
Ho AS, Chen CH, Cheng CC, Wang CC, Lin HC, Luo TY, Lien GS, Chang J. Neutrophil elastase as a diagnostic marker and therapeutic target in colorectal cancers. Oncotarget. 2014;5(2):473–80. https://doi.org/10.18632/oncotarget.1631. PMID: 24457622; PMCID: PMC3964222.
Google Scholar
Foekens JA, Ries C, Look MP, Gippner-Steppert C, Klijn JG, Jochum M. The prognostic value of polymorphonuclear leukocyte elastase in patients with primary breast cancer. Cancer Res. 2003;63(2):337–41. PMID: 12543785.
Google Scholar
Lerman I, Garcia-Hernandez ML, Rangel-Moreno J, Chiriboga L, Pan C, Nastiuk KL, Krolewski JJ, Sen A, Hammes SR. Infiltrating myeloid cells exert protumorigenic actions via neutrophil elastase. Mol Cancer Res. 2017;15(9):1138–52. https://doi.org/10.1158/1541-7786.MCR-17-0003. Epub 2017 May 16. PMID: 28512253; PMCID: PMC5581693.
Google Scholar
Zeng W, Song Y, Wang R, He R, Wang T. Neutrophil elastase: from mechanisms to therapeutic potential. J Pharm Anal. 2023;13(4):355–66. https://doi.org/10.1016/j.jpha.2022.12.003. Epub 2023 Jan 7. PMID: 37181292; PMCID: PMC10173178.
Google Scholar
Wada Y, Yoshida K, Tsutani Y, Shigematsu H, Oeda M, Sanada Y, Suzuki T, Mizuiri H, Hamai Y, Tanabe K, Ukon K, Hihara J. Neutrophil elastase induces cell proliferation and migration by the release of TGF-alpha, PDGF and VEGF in esophageal cell lines. Oncol Rep. 2007;17(1):161–7. PMID: 17143494.
Google Scholar
Wada Y, Yoshida K, Hihara J, Konishi K, Tanabe K, Ukon K, Taomoto J, Suzuki T, Mizuiri H. Sivelestat, a specific neutrophil elastase inhibitor, suppresses the growth of gastric carcinoma cells by preventing the release of transforming growth factor-alpha. Cancer Sci. 2006;97(10):1037–43. https://doi.org/10.1111/j.1349-7006.2006.00278.x. Epub 2006 Aug 17. PMID: 16918998; PMCID: PMC11158772.
Google Scholar
Lerman I, Hammes SR. Neutrophil elastase in the tumor microenvironment. Steroids. 2018;133:96–101. https://doi.org/10.1016/j.steroids.2017.11.006. Epub 2017 Nov 16. PMID: 29155217; PMCID: PMC5870895.
Google Scholar
Pivetta E, Danussi C, Wassermann B, Modica TM, Del Bel Belluz L, Canzonieri V, Colombatti A, Spessotto P. Neutrophil elastase-dependent cleavage compromises the tumor suppressor role of EMILIN1. Matrix Biol. 2014;34:22–32. Epub 2014 Feb 7. PMID: 24513040.
Google Scholar
Maiorani O, Pivetta E, Capuano A, Modica TM, Wassermann B, Bucciotti F, Colombatti A, Doliana R, Spessotto P. Neutrophil elastase cleavage of the gC1q domain impairs the EMILIN1-α4β1 integrin interaction, cell adhesion and anti-proliferative activity. Sci Rep. 2017;7:39974. https://doi.org/10.1038/srep39974. PMID: 28074935; PMCID: PMC5225433.
Google Scholar
El Rayes T, Catena R, Lee S, Stawowczyk M, Joshi N, Fischbach C, Powell CA, Dannenberg AJ, Altorki NK, Gao D, Mittal V. Lung inflammation promotes metastasis through neutrophil protease-mediated degradation of Tsp-1. Proc Natl Acad Sci U S A. 2015;112(52):16000–5. https://doi.org/10.1073/pnas.1507294112. Epub 2015 Dec 14. PMID: 26668367; PMCID: PMC4703007.
Google Scholar
Tamakuma S, Ogawa M, Aikawa N, Kubota T, Hirasawa H, Ishizaka A, Taenaka N, Hamada C, Matsuoka S, Abiru T. Relationship between neutrophil elastase and acute lung injury in humans. Pulm Pharmacol Ther. 2004;17(5):271–9. https://doi.org/10.1016/j.pupt.2004.05.003. PMID: 15477122.
Matsuzaki K, Hiramatsu Y, Homma S, Sato S, Shigeta O, Sakakibara Y. Sivelestat reduces inflammatory mediators and preserves neutrophil deformability during simulated extracorporeal circulation. Ann Thorac Surg. 2005;80(2):611–7. https://doi.org/10.1016/j.athoracsur.2005.02.038. PMID: 16039215.
Aikawa N, Kawasaki Y. Clinical utility of the neutrophil elastase inhibitor Sivelestat for the treatment of acute respiratory distress syndrome. Ther Clin Risk Manag. 2014;10:621–9. https://doi.org/10.2147/TCRM.S65066. PMID: 25120368; PMCID: PMC4130327.
Google Scholar
Okamoto M, Mizuno R, Kawada K, Itatani Y, Kiyasu Y, Hanada K, Hirata W, Nishikawa Y, Masui H, Sugimoto N, Tamura T, Inamoto S, Sakai Y, Obama K. Neutrophil extracellular traps promote metastases of colorectal cancers through activation of ERK signaling by releasing neutrophil elastase. Int J Mol Sci. 2023;24(2):1118. https://doi.org/10.3390/ijms24021118. PMID: 36674635; PMCID: PMC9867023.
Google Scholar
Rayes RF, Mouhanna JG, Nicolau I, Bourdeau F, Giannias B, Rousseau S, Quail D, Walsh L, Sangwan V, Bertos N, Cools-Lartigue J, Ferri LE, Spicer JD. Primary tumors induce neutrophil extracellular traps with targetable metastasis promoting effects. JCI Insight. 2019;5(16):e128008. https://doi.org/10.1172/jci.insight.128008. PMID: 31343990; PMCID: PMC6777835.
Google Scholar
Silva CMS, Wanderley CWS, Veras FP, Sonego F, Nascimento DC, Gonçalves AV, Martins TV, Cólon DF, Borges VF, Brauer VS, Damasceno LEA, Silva KP, Toller-Kawahisa JE, Batah SS, Souza ALJ, Monteiro VS, Oliveira AER, Donate PB, Zoppi D, Borges MC, Almeida F, Nakaya HI, Fabro AT, Cunha TM, Alves-Filho JC, Zamboni DS, Cunha FQ. Gasdermin D Inhibition prevents multiple organ dysfunction during sepsis by blocking NET formation. Blood. 2021;138(25):2702–13. https://doi.org/10.1182/blood.2021011525. PMID: 34407544; PMCID: PMC8703366.
Google Scholar
Jia W, Mao Y, Luo Q, Wu J, Guan Q. Targeting neutrophil elastase is a promising direction for future cancer treatment. Discov Oncol. 2024;15(1):167. https://doi.org/10.1007/s12672-024-01010-3. PMID: 38750338; PMCID: PMC11096153.
Google Scholar
Cui C, Chakraborty K, Tang XA, Zhou G, Schoenfelt KQ, Becker KM, Hoffman A, Chang YF, Blank A, Reardon CA, Kenny HA, Vaisar T, Lengyel E, Greene G, Becker L. Neutrophil elastase selectively kills cancer cells and attenuates tumorigenesis. Cell. 2021;184(12):3163–e317721. Epub 2021 May 7. PMID: 33964209; PMCID: PMC10712736.
Google Scholar
Eruslanov EB, Singhal S, Albelda SM. Mouse versus human neutrophils in cancer: A major knowledge gap. Trends Cancer. 2017;3(2):149–60. https://doi.org/10.1016/j.trecan.2016.12.006. Epub 2017 Jan 19. PMID: 28718445; PMCID: PMC5518602.
Google Scholar
Kessenbrock K, Plaks V, Werb Z. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell. 2010;141(1):52–67. https://doi.org/10.1016/j.cell.2010.03.015. PMID: 20371345; PMCID: PMC2862057.
Google Scholar
Mondal S, Adhikari N, Banerjee S, Amin SA, Jha T. Matrix metalloproteinase-9 (MMP-9) and its inhibitors in cancer: A minireview. Eur J Med Chem. 2020;194:112260. https://doi.org/10.1016/j.ejmech.2020.112260. Epub 2020 Mar 21. Erratum in: Eur J Med Chem. 2020;205:112642. https://doi.org/10.1016/j.ejmech.2020.112642. PMID: 32224379.
Cai N, Cheng K, Ma Y, Liu S, Tao R, Li Y, Li D, Guo B, Jia W, Liang H, Zhao J, Xia L, Ding ZY, Chen J, Zhang W. Targeting MMP9 in CTNNB1 mutant hepatocellular carcinoma restores CD8 + T cell-mediated antitumour immunity and improves anti-PD-1 efficacy. Gut. 2024;73(6):985–99. https://doi.org/10.1136/gutjnl-2023-331342. PMID: 38123979; PMCID: PMC11103337.
Google Scholar
Lee CJ, Jang TY, Jeon SE, Yun HJ, Cho YH, Lim DY, Nam JS. The dysadherin/MMP9 axis modifies the extracellular matrix to accelerate colorectal cancer progression. Nat Commun. 2024;15(1):10422. https://doi.org/10.1038/s41467-024-54920-9. PMID: 39613801; PMCID: PMC11607440.
Google Scholar
Bories D, Raynal MC, Solomon DH, Darzynkiewicz Z, Cayre YE. Down-regulation of a serine protease, myeloblastin, causes growth arrest and differentiation of promyelocytic leukemia cells. Cell. 1989;59(6):959–68. https://doi.org/10.1016/0092-8674(89)90752-6. PMID: 2598267.
Google Scholar
Campanelli D, Detmers PA, Nathan CF, Gabay JE. Azurocidin and a homologous Serine protease from neutrophils. Differential antimicrobial and proteolytic properties. J Clin Invest. 1990;85(3):904–15. PMID: 2312733; PMCID: PMC296509.
Google Scholar
Coeshott C, Ohnemus C, Pilyavskaya A, Ross S, Wieczorek M, Kroona H, Leimer AH, Cheronis J. Converting enzyme-independent release of tumor necrosis factor alpha and IL-1beta from a stimulated human monocytic cell line in the presence of activated neutrophils or purified proteinase 3. Proc Natl Acad Sci U S A. 1999;96(11):6261–6. https://doi.org/10.1073/pnas.96.11.6261. PMID: 10339575; PMCID: PMC26869.
Google Scholar
Mehlen P, Puisieux A. Metastasis: a question of life or death. Nat Rev Cancer. 2006;6(6):449–58. https://doi.org/10.1038/nrc1886. PMID: 16723991.
Google Scholar
Schneider C, Fehr MK, Steiner RA, Hagen D, Haller U, Fink D. Frequency and distribution pattern of distant metastases in breast cancer patients at the time of primary presentation. Arch Gynecol Obstet. 2003;269(1):9–12. https://doi.org/10.1007/s00404-002-0445-x. Epub 2002 Nov 15. PMID: 14605816.
Google Scholar
Baggiolini M, Bretz U, Dewald B, Feigenson ME. The polymorphonuclear leukocyte. Agents Actions. 1978;8(1–2):3–10. https://doi.org/10.1007/BF01972395. PMID: 345782.
Google Scholar
Pham CT. Neutrophil serine proteases: specific regulators of inflammation. Nat Rev Immunol. 2006;6(7):541–50. https://doi.org/10.1038/nri1841. PMID: 16799473.
Cox TR. The matrix in cancer. Nat Rev Cancer. 2021;21(4):217–38. https://doi.org/10.1038/s41568-020-00329-7. Epub 2021 Feb 15. PMID: 33589810.
Google Scholar
Guan X, Lu Y, Zhu H, Yu S, Zhao W, Chi X, Xie C, Yin Z. The crosstalk between cancer cells and neutrophils enhances hepatocellular carcinoma metastasis via neutrophil extracellular Traps-Associated cathepsin G component: A potential therapeutic target. J Hepatocell Carcinoma. 2021;8:451–65. PMID: 34046369; PMCID: PMC8144903.
Google Scholar
Fu Z, Akula S, Thorpe M, Hellman L. Potent and broad but not unselective cleavage of cytokines and chemokines by human neutrophil elastase and proteinase 3. Int J Mol Sci. 2020;21(2):651. https://doi.org/10.3390/ijms21020651. PMID: 31963828; PMCID: PMC7014372.
Google Scholar
Burster T, Knippschild U, Molnár F, Zhanapiya A. Cathepsin G and its Dichotomous Role in Modulating Levels of MHC Class I Molecules. Arch Immunol Ther Exp (Warsz). 2020;68(4):25. https://doi.org/10.1007/s00005-020-00585-3. PMID: 32815043.
Kudo T, Kigoshi H, Hagiwara T, Takino T, Yamazaki M, Yui S, Cathepsin G. A neutrophil protease, induces compact cell-cell adhesion in MCF-7 human breast cancer cells. Mediators Inflamm. 2009;2009:850940. https://doi.org/10.1155/2009/850940. Epub 2009 Nov 10. PMID: 19920860; PMCID: PMC2775934.
Google Scholar
Song Y, Jin D, Chen J, Luo Z, Chen G, Yang Y, Liu X. Identification of an immune-related long non-coding RNA signature and nomogram as prognostic target for muscle-invasive bladder cancer. Aging. 2020;12(12):12051–73. https://doi.org/10.18632/aging.103369. Epub 2020 Jun 24. PMID: 32579540; PMCID: PMC7343518.
Google Scholar
Chan S, Wang X, Wang Z, Du Y, Zuo X, Chen J, Sun R, Zhang Q, Lin L, Yang Y, Yu Z, Zhao H, Zhang H, Chen W. CTSG suppresses colorectal cancer progression through negative regulation of Akt/mTOR/Bcl2 signaling pathway. Int J Biol Sci. 2023;19(7):2220–33. https://doi.org/10.7150/ijbs.82000. PMID: 37151875; PMCID: PMC10158020.
Google Scholar
Shi L, Yao H, Liu Z, Xu M, Tsung A, Wang Y. Endogenous PAD4 in breast cancer cells mediates cancer extracellular chromatin network formation and promotes lung metastasis. Mol Cancer Res. 2020;18(5):735–47. https://doi.org/10.1158/1541-7786.MCR-19-0018. Epub 2020 Mar 19. PMID: 32193354; PMCID: PMC7668292.
Google Scholar
Chang X, Han J. Expression of peptidylarginine deiminase type 4 (PAD4) in various tumors. Mol Carcinog. 2006;45(3):183 – 96. https://doi.org/10.1002/mc.20169. PMID: 16355400.
Chang X, Han J, Pang L, Zhao Y, Yang Y, Shen Z. Increased PADI4 expression in blood and tissues of patients with malignant tumors. BMC Cancer. 2009;9:40. https://doi.org/10.1186/1471-2407-9-40. PMID: 19183436; PMCID: PMC2637889.
Yuzhalin AE, Gordon-Weeks AN, Tognoli ML, Jones K, Markelc B, Konietzny R, Fischer R, Muth A, O’Neill E, Thompson PR, Venables PJ, Kessler BM, Lim SY, Muschel RJ. Colorectal cancer liver metastatic growth depends on PAD4-driven citrullination of the extracellular matrix. Nat Commun. 2018;9(1):4783. https://doi.org/10.1038/s41467-018-07306-7. PMID: 30429478; PMCID: PMC6235861.
Google Scholar
Wang Y, Lyu Y, Tu K, Xu Q, Yang Y, Salman S, Le N, Lu H, Chen C, Zhu Y, Wang R, Liu Q, Semenza GL. Histone citrullination by PADI4 is required for HIF-dependent transcriptional responses to hypoxia and tumor vascularization. Sci Adv. 2021;7(35):eabe3771. https://doi.org/10.1126/sciadv.abe3771. PMID: 34452909; PMCID: PMC8397272.
Google Scholar
Liu K, Zhang Y, Du G, Chen X, Xiao L, Jiang L, Jing N, Xu P, Zhao C, Liu Y, Zhao H, Sun Y, Wang J, Cheng C, Wang D, Pan J, Xue W, Zhang P, Zhang ZG, Gao WQ, Jiang SH, Zhang K, Zhu HH. 5-HT orchestrates histone serotonylation and citrullination to drive neutrophil extracellular traps and liver metastasis. J Clin Invest. 2025;135(8):e183544. https://doi.org/10.1172/JCI183544. PMID: 39903533; PMCID: PMC11996869.
Google Scholar
Zhu D, Lu Y, Yan Z, Deng Q, Hu B, Wang Y, Wang W, Wang Y, Wang Y. A β-Carboline derivate PAD4 inhibitor reshapes neutrophil phenotype and improves the tumor immune microenvironment against Triple-Negative breast cancer. J Med Chem. 2024;67(10):7973–94. https://doi.org/10.1021/acs.jmedchem.4c00030. Epub 2024 May 10. PMID: 38728549.
Google Scholar
Tan H, Jiang Y, Shen L, Nuerhashi G, Wen C, Gu L, Wang Y, Qi H, Cao F, Huang T, Liu Y, Xie W, Deng W, Fan W. Cryoablation-induced neutrophil Ca2 + elevation and NET formation exacerbate immune escape in colorectal cancer liver metastasis. J Exp Clin Cancer Res. 2024;43(1):319. https://doi.org/10.1186/s13046-024-03244-z. PMID: 39648199; PMCID: PMC11626751.
Google Scholar
Luo Y, Arita K, Bhatia M, Knuckley B, Lee YH, Stallcup MR, Sato M, Thompson PR. Inhibitors and inactivators of protein arginine deiminase 4: functional and structural characterization. Biochemistry. 2006;45(39):11727–36. https://doi.org/10.1021/bi061180d. PMID: 17002273; PMCID: PMC1808342.
Google Scholar
Cedervall J, Dragomir A, Saupe F, Zhang Y, Ärnlöv J, Larsson E, Dimberg A, Larsson A, Olsson AK. Pharmacological targeting of peptidylarginine deiminase 4 prevents cancer-associated kidney injury in mice. Oncoimmunology. 2017;6(8):e1320009. PMID: 28919990; PMCID: PMC5593702.
Google Scholar
Zhou Y, An LL, Chaerkady R, Mittereder N, Clarke L, Cohen TS, Chen B, Hess S, Sims GP, Mustelin T. Evidence for a direct link between PAD4-mediated citrullination and the oxidative burst in human neutrophils. Sci Rep. 2018;8(1):15228. https://doi.org/10.1038/s41598-018-33385-z. PMID: 30323221; PMCID: PMC6189209.
Google Scholar
Mollica Poeta V, Massara M, Capucetti A, Bonecchi R. Chemokines and chemokine receptors: new targets for cancer immunotherapy. Front Immunol. 2019;10:379. https://doi.org/10.3389/fimmu.2019.00379. PMID: 30894861; PMCID: PMC6414456.
Google Scholar
Nie M, Yang L, Bi X, Wang Y, Sun P, Yang H, Liu P, Li Z, Xia Y, Jiang W. Neutrophil extracellular traps induced by IL8 promote diffuse large B-cell lymphoma progression via the TLR9 signaling. Clin Cancer Res. 2019;25(6):1867–79. https://doi.org/10.1158/1078-0432.CCR-18-1226. Epub 2018 Nov 16. PMID: 30446590.
Google Scholar
Bullock K, Richmond A. Suppressing MDSC recruitment to the tumor microenvironment by antagonizing CXCR2 to enhance the efficacy of immunotherapy. Cancers (Basel). 2021;13(24):6293. https://doi.org/10.3390/cancers13246293. PMID: 34944914; PMCID: PMC8699249.
Google Scholar
Sano M, Ijichi H, Takahashi R, Miyabayashi K, Fujiwara H, Yamada T, Kato H, Nakatsuka T, Tanaka Y, Tateishi K, Morishita Y, Moses HL, Isayama H, Koike K. Blocking CXCLs-CXCR2 axis in tumor-stromal interactions contributes to survival in a mouse model of pancreatic ductal adenocarcinoma through reduced cell invasion/migration and a shift of immune-inflammatory microenvironment. Oncogenesis. 2019;8(2):8. https://doi.org/10.1038/s41389-018-0117-8. PMID: 30659170; PMCID: PMC6338726.
Google Scholar
Gulhati P, Schalck A, Jiang S, Shang X, Wu CJ, Hou P, Ruiz SH, Soto LS, Parra E, Ying H, Han J, Dey P, Li J, Deng P, Sei E, Maeda DY, Zebala JA, Spring DJ, Kim M, Wang H, Maitra A, Moore D, Clise-Dwyer K, Wang YA, Navin NE, DePinho RA. Targeting T cell checkpoints 41BB and LAG3 and myeloid cell CXCR1/CXCR2 results in antitumor immunity and durable response in pancreatic cancer. Nat Cancer. 2023;4(1):62–80. https://doi.org/10.1038/s43018-022-00500-z. Epub 2022 Dec 30. PMID: 36585453; PMCID: PMC9925045.
Google Scholar
Nywening TM, Belt BA, Cullinan DR, Panni RZ, Han BJ, Sanford DE, Jacobs RC, Ye J, Patel AA, Gillanders WE, Fields RC, DeNardo DG, Hawkins WG, Goedegebuure P, Linehan DC. Targeting both tumour-associated CXCR2 + neutrophils and CCR2 + macrophages disrupts myeloid recruitment and improves chemotherapeutic responses in pancreatic ductal adenocarcinoma. Gut. 2018;67(6):1112–23. https://doi.org/10.1136/gutjnl-2017-313738. Epub 2017 Dec 1. PMID: 29196437; PMCID: PMC5969359.
Google Scholar
Cheng Y, Mo F, Li Q, Han X, Shi H, Chen S, Wei Y, Wei X. Targeting CXCR2 inhibits the progression of lung cancer and promotes therapeutic effect of cisplatin. Mol Cancer. 2021;20(1):62. https://doi.org/10.1186/s12943-021-01355-1. PMID: 33814009; PMCID: PMC8019513.
Google Scholar
Pant A, Hwa-Lin Bergsneider B, Srivastava S, Kim T, Jain A, Bom S, Shah P, Kannapadi N, Patel K, Choi J, Cho KB, Verma R, Yu-Ju Wu C, Brem H, Tyler B, Pardoll DM, Jackson C, Lim M. CCR2 and CCR5 co-inhibition modulates immunosuppressive myeloid milieu in glioma and synergizes with anti-PD-1 therapy. Oncoimmunology. 2024;13(1):2338965. PMID: 38590799; PMCID: PMC11000615.
Google Scholar
Chao CC, Lee CW, Chang TM, Chen PC, Liu JF. CXCL1/CXCR2 paracrine axis contributes to lung metastasis in osteosarcoma. Cancers (Basel). 2020;12(2):459. https://doi.org/10.3390/cancers12020459. PMID: 32079335; PMCID: PMC7072404.
Google Scholar
Li YM, Liu ZY, Wang JC, Yu JM, Li ZC, Yang HJ, Tang J, Chen ZN. Receptor-Interacting protein kinase 3 deficiency recruits Myeloid-Derived suppressor cells to hepatocellular carcinoma through the chemokine (C-X-C Motif) ligand 1-Chemokine (C-X-C Motif) receptor 2 axis. Hepatology. 2019;70(5):1564–81. Epub 2019 Jul 17. PMID: 31021443; PMCID: PMC6900048.
Google Scholar
Dahmani A, Delisle JS. TGF-β in T cell biology: implications for cancer immunotherapy. Cancers (Basel). 2018;10(6):194. https://doi.org/10.3390/cancers10060194. PMID: 29891791; PMCID: PMC6025055.
Google Scholar
Suzuki E, Kim S, Cheung HK, Corbley MJ, Zhang X, Sun L, Shan F, Singh J, Lee WC, Albelda SM, Ling LE. A novel small-molecule inhibitor of transforming growth factor beta type I receptor kinase (SM16) inhibits murine mesothelioma tumor growth in vivo and prevents tumor recurrence after surgical resection. Cancer Res. 2007;67(5):2351–9. https://doi.org/10.1158/0008-5472.CAN-06-2389. PMID: 17332368.
Google Scholar
Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L, Worthen GS, Albelda SM. Polarization of tumor-associated neutrophil phenotype by TGF-beta: N1 versus N2 TAN. Cancer Cell. 2009;16(3):183–94. PMID: 19732719; PMCID: PMC2754404.
Google Scholar
Chung JY, Chan MK, Li JS, Chan AS, Tang PC, Leung KT, To KF, Lan HY, Tang PM. TGF-β signaling: from tissue fibrosis to tumor microenvironment. Int J Mol Sci. 2021;22(14):7575. https://doi.org/10.3390/ijms22147575. PMID: 34299192; PMCID: PMC8303588.
Google Scholar
Chan MK, Chung JY, Tang PC, Chan AS, Ho JY, Lin TP, Chen J, Leung KT, To KF, Lan HY, Tang PM. TGF-β signaling networks in the tumor microenvironment. Cancer Lett. 2022;550:215925. https://doi.org/10.1016/j.canlet.2022.215925. Epub 2022 Sep 29. PMID: 36183857.
Google Scholar
Chung JY, Tang PC, Chan MK, Xue VW, Huang XR, Ng CS, Zhang D, Leung KT, Wong CK, Lee TL, Lam EW, Nikolic-Paterson DJ, To KF, Lan HY, Tang PM. Smad3 is essential for polarization of tumor-associated neutrophils in non-small cell lung carcinoma. Nat Commun. 2023;14(1):1794. https://doi.org/10.1038/s41467-023-37515-8. PMID: 37002229; PMCID: PMC10066366.
Google Scholar
Tang PM, Zhou S, Meng XM, Wang QM, Li CJ, Lian GY, Huang XR, Tang YJ, Guan XY, Yan BP, To KF, Lan HY. Smad3 promotes cancer progression by inhibiting E4BP4-mediated NK cell development. Nat Commun. 2017;8:14677. https://doi.org/10.1038/ncomms14677. PMID: 28262747; PMCID: PMC5343519.
Google Scholar
Peng H, Shen J, Long X, Zhou X, Zhang J, Xu X, Huang T, Xu H, Sun S, Li C, Lei P, Wu H, Zhao J. Local release of TGF-β inhibitor modulates Tumor-Associated neutrophils and enhances pancreatic cancer response to combined irreversible electroporation and immunotherapy. Adv Sci (Weinh). 2022;9(10):e2105240. https://doi.org/10.1002/advs.202105240. Epub 2022 Feb 7. PMID: 35128843; PMCID: PMC8981446.
Google Scholar
Pei Y, Chen L, Huang Y, Wang J, Feng J, Xu M, Chen Y, Song Q, Jiang G, Gu X, Zhang Q, Gao X, Chen J. Sequential targeting TGF-β signaling and KRAS mutation increases therapeutic efficacy in pancreatic cancer. Small. 2019;15(24):e1900631. https://doi.org/10.1002/smll.201900631. Epub 2019 Apr 29. PMID: 31033217.
Google Scholar
Chen Z, Zhang H, Qu M, Nan K, Cao H, Cata JP, Chen W, Miao C. Review: the emerging role of neutrophil extracellular traps in sepsis and sepsis-Associated thrombosis. Front Cell Infect Microbiol. 2021;11:653228. PMID: 33816356; PMCID: PMC8010653.
Google Scholar
Hisada Y, Grover SP, Maqsood A, Houston R, Ay C, Noubouossie DF, Cooley BC, Wallén H, Key NS, Thålin C, Farkas ÁZ, Farkas VJ, Tenekedjiev K, Kolev K, Mackman N. Neutrophils and neutrophil extracellular traps enhance venous thrombosis in mice bearing human pancreatic tumors. Haematologica. 2020;105(1):218–25. Epub 2019 May 2. PMID: 31048354; PMCID: PMC6939515.
Google Scholar
Kim SW, Lee JK. Role of HMGB1 in the interplay between NETosis and thrombosis in ischemic stroke: A review. Cells. 2020;9(8):1794. https://doi.org/10.3390/cells9081794. PMID: 32731558; PMCID: PMC7464684.
Google Scholar
Spicer JD, McDonald B, Cools-Lartigue JJ, Chow SC, Giannias B, Kubes P, Ferri LE. Neutrophils promote liver metastasis via Mac-1-mediated interactions with Circulating tumor cells. Cancer Res. 2012;72(16):3919–27. https://doi.org/10.1158/0008-5472.CAN-11-2393. Epub 2012 Jul 2. PMID: 22751466.
Google Scholar
Szczerba BM, Castro-Giner F, Vetter M, Krol I, Gkountela S, Landin J, Scheidmann MC, Donato C, Scherrer R, Singer J, Beisel C, Kurzeder C, Heinzelmann-Schwarz V, Rochlitz C, Weber WP, Beerenwinkel N, Aceto N. Neutrophils escort Circulating tumour cells to enable cell cycle progression. Nature. 2019;566(7745):553–7. https://doi.org/10.1038/s41586-019-0915-y. Epub 2019 Feb 6. PMID: 30728496.
Google Scholar
Bianchi M, Sun M, Jeldres C, Shariat SF, Trinh QD, Briganti A, Tian Z, Schmitges J, Graefen M, Perrotte P, Menon M, Montorsi F, Karakiewicz PI. Distribution of metastatic sites in renal cell carcinoma: a population-based analysis. Ann Oncol. 2012;23(4):973–80. https://doi.org/10.1093/annonc/mdr362. Epub 2011 Sep 2. PMID: 21890909.
Google Scholar