DeNardo, D. G. & Ruffell, B. Macrophages as regulators of tumour immunity and immunotherapy. Nat. Rev. Immunol. 19, 369–382 (2019).
Google Scholar
Swann, J. W., Olson, O. C. & Passegue, E. Made to order: emergency myelopoiesis and demand-adapted innate immune cell production. Nat. Rev. Immunol. 24, 596–613 (2024).
Google Scholar
Goswami, S., Anandhan, S., Raychaudhuri, D. & Sharma, P. Myeloid cell-targeted therapies for solid tumours. Nat. Rev. Immunol. 23, 106–120 (2023).
Google Scholar
Sica, A., Guarneri, V. & Gennari, A. Myelopoiesis, metabolism and therapy: a crucial crossroads in cancer progression. Cell Stress 3, 284–294 (2019).
Google Scholar
Giles, A. J. et al. Activation of hematopoietic stem/progenitor cells promotes immunosuppression within the pre-metastatic niche. Cancer Res. 76, 1335–1347 (2016).
Google Scholar
Casbon, A. J. et al. Invasive breast cancer reprograms early myeloid differentiation in the bone marrow to generate immunosuppressive neutrophils. Proc. Natl Acad. Sci. USA 112, E566–E575 (2015).
Google Scholar
Wu, W. C. et al. Circulating hematopoietic stem and progenitor cells are myeloid-biased in cancer patients. Proc. Natl Acad. Sci. USA 111, 4221–4226 (2014).
Google Scholar
Porembka, M. R. et al. Pancreatic adenocarcinoma induces bone marrow mobilization of myeloid-derived suppressor cells which promote primary tumor growth. Cancer Immunol. Immunother. 61, 1373–1385 (2012).
Google Scholar
Trzebanski, S. et al. Classical monocyte ontogeny dictates their functions and fates as tissue macrophages. Immunity 57, 1225–1243 (2024).
Google Scholar
Ikeda, N. et al. The early neutrophil-committed progenitors aberrantly differentiate into immunoregulatory monocytes during emergency myelopoiesis. Cell Rep. 42, 112165 (2023).
Google Scholar
LaMarche, N. M. et al. An IL-4 signalling axis in bone marrow drives pro-tumorigenic myelopoiesis. Nature 625, 166–174 (2024).
Google Scholar
Hao, X. et al. Osteoprogenitor–GMP crosstalk underpins solid tumor-induced systemic immunosuppression and persists after tumor removal. Cell Stem Cell 30, 648–664 (2023).
Google Scholar
Gerber-Ferder, Y. et al. Breast cancer remotely imposes a myeloid bias on haematopoietic stem cells by reprogramming the bone marrow niche. Nat. Cell Biol. 25, 1736–1745 (2023).
Google Scholar
Dey, S., Curtis, D. J., Jane, S. M. & Brandt, S. J. The TAL1/SCL transcription factor regulates cell cycle progression and proliferation in differentiating murine bone marrow monocyte precursors. Mol. Cell. Biol. 30, 2181–2192 (2010).
Google Scholar
Pham, T. H. et al. Dynamic epigenetic enhancer signatures reveal key transcription factors associated with monocytic differentiation states. Blood 119, e161–e171 (2012).
Google Scholar
Mandula, J. K. & Rodriguez, P. C. Tumor-related stress regulates functional plasticity of MDSCs. Cell Immunol. 363, 104312 (2021).
Google Scholar
Paul, F. et al. Transcriptional heterogeneity and lineage commitment in myeloid progenitors. Cell 163, 1663–1677 (2015).
Google Scholar
Kwart, D. et al. Cancer cell-derived type I interferons instruct tumor monocyte polarization. Cell Rep. 41, 111769 (2022).
Google Scholar
Alicea-Torres, K. et al. Immune suppressive activity of myeloid-derived suppressor cells in cancer requires inactivation of the type I interferon pathway. Nat. Commun. 12, 1717 (2021).
Google Scholar
Kwak, H. J. et al. Myeloid cell-derived reactive oxygen species externally regulate the proliferation of myeloid progenitors in emergency granulopoiesis. Immunity 42, 159–171 (2015).
Google Scholar
Pizzato, H. A. et al. Mitochondrial pyruvate metabolism and glutaminolysis toggle steady-state and emergency myelopoiesis. J. Exp. Med. 220, e20221373 (2023).
Google Scholar
Pietras, E. M. et al. Re-entry into quiescence protects hematopoietic stem cells from the killing effect of chronic exposure to type I interferons. J. Exp. Med. 211, 245–262 (2014).
Google Scholar
Molgora, M. et al. TREM2 modulation remodels the tumor myeloid landscape enhancing anti-PD-1 immunotherapy. Cell 182, 886–900 (2020).
Google Scholar
Katzenelenbogen, Y. et al. Coupled scRNA-seq and intracellular protein activity reveal an immunosuppressive role of TREM2 in cancer. Cell 182, 872–885 (2020).
Google Scholar
Matusiak, M. et al. Spatially segregated macrophage populations predict distinct outcomes in colon cancer. Cancer Discov. 14, 1418–1439 (2024).
Google Scholar
Mulder, K. et al. Cross-tissue single-cell landscape of human monocytes and macrophages in health and disease. Immunity 54, 1883–1900 (2021).
Google Scholar
McGinnis, C. S. et al. The temporal progression of lung immune remodeling during breast cancer metastasis. Cancer Cell 42, 1018–1031 (2024).
Google Scholar
Beury, D. W. et al. Myeloid-derived suppressor cell survival and function are regulated by the transcription factor Nrf2. J. Immunol. 196, 3470–3478 (2016).
Google Scholar
Namgaladze, D., Fuhrmann, D. C. & Brune, B. Interplay of Nrf2 and BACH1 in inducing ferroportin expression and enhancing resistance of human macrophages towards ferroptosis. Cell Death Discov. 8, 327 (2022).
Google Scholar
Kobayashi, E. H. et al. Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription. Nat. Commun. 7, 11624 (2016).
Google Scholar
Ryan, D. G. et al. Nrf2 activation reprograms macrophage intermediary metabolism and suppresses the type I interferon response. iScience 25, 103827 (2022).
Google Scholar
Olagnier, D. et al. Nrf2 negatively regulates STING indicating a link between antiviral sensing and metabolic reprogramming. Nat. Commun. 9, 3506 (2018).
Google Scholar
Ting, K. K. Y. et al. Oxidized low-density lipoprotein accumulation suppresses glycolysis and attenuates the macrophage inflammatory response by diverting transcription from the HIF-1alpha to the Nrf2 pathway. J. Immunol. 211, 1561–1577 (2023).
Google Scholar
Park, M. D. et al. TREM2 macrophages drive NK cell paucity and dysfunction in lung cancer. Nat. Immunol. 24, 792–801 (2023).
Google Scholar
Alaluf, E. et al. Heme oxygenase-1 orchestrates the immunosuppressive program of tumor-associated macrophages. JCI Insight 5, e133929 (2020).
Google Scholar
Leader, A. M. et al. Single-cell analysis of human non-small cell lung cancer lesions refines tumor classification and patient stratification. Cancer Cell 39, 1594–1609 (2021).
Google Scholar
Hu, J. et al. Tumor microenvironment remodeling after neoadjuvant immunotherapy in non-small cell lung cancer revealed by single-cell RNA sequencing. Genome Med. 15, 14 (2023).
Google Scholar
Zelenay, S. et al. Cyclooxygenase-dependent tumor growth through evasion of immunity. Cell 162, 1257–1270 (2015).
Google Scholar
Taniguchi, S. et al. In vivo induction of activin A-producing alveolar macrophages supports the progression of lung cell carcinoma. Nat. Commun. 14, 143 (2023).
Google Scholar
Gomez-Chou, S. B. et al. Lipocalin-2 promotes pancreatic ductal adenocarcinoma by regulating inflammation in the tumor microenvironment. Cancer Res. 77, 2647–2660 (2017).
Google Scholar
Li, Z. et al. Proinflammatory S100A8 induces PD-L1 expression in macrophages, mediating tumor immune escape. J. Immunol. 204, 2589–2599 (2020).
Google Scholar
Uccellini, M. B. & Garcia-Sastre, A. ISRE-reporter mouse reveals high basal and induced type I IFN responses in inflammatory monocytes. Cell Rep. 25, 2784–2796 (2018).
Google Scholar
Singh, A. et al. Small molecule inhibitor of NRF2 selectively intervenes therapeutic resistance in KEAP1-deficient NSCLC tumors. ACS Chem. Biol. 11, 3214–3225 (2016).
Google Scholar
Schaer, D. J. et al. Hemorrhage-activated NRF2 in tumor-associated macrophages drives cancer growth, invasion, and immunotherapy resistance. J. Clin. Invest. 134, e174528 (2023).
Google Scholar
Liu, Z. et al. Fate mapping via Ms4a3-expression history traces monocyte-derived cells. Cell 178, 1509–1525 (2019).
Google Scholar
Ren, D. et al. Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism. Proc. Natl Acad. Sci. USA 108, 1433–1438 (2011).
Google Scholar
Perrone, M. et al. ATF3 reprograms the bone marrow niche in response to early breast cancer transformation. Cancer Res. 83, 117–129 (2023).
Google Scholar
Zhang, M. et al. Selective activation of STAT3 and STAT5 dictates the fate of myeloid progenitor cells. Cell Death Discov. 9, 274 (2023).
Google Scholar
Laurenti, E. et al. Hematopoietic stem cell function and survival depend on c-Myc and N-Myc activity. Cell Stem Cell 3, 611–624 (2008).
Google Scholar
Villar, J. et al. ETV3 and ETV6 enable monocyte differentiation into dendritic cells by repressing macrophage fate commitment. Nat. Immunol. 24, 84–95 (2023).
Google Scholar
Ratajczak, M. Z. & Kucia, M. Hematopoiesis and innate immunity: an inseparable couple for good and bad times, bound together by an hormetic relationship. Leukemia 36, 23–32 (2022).
Google Scholar
Ng, M. S. F. et al. Deterministic reprogramming of neutrophils within tumors. Science 383, eadf6493 (2024).
Google Scholar
Zhao, Y. et al. Neutrophils resist ferroptosis and promote breast cancer metastasis through aconitate decarboxylase 1. Cell Metab. 35, 1688–1703 (2023).
Google Scholar
Garner, H. et al. Understanding and reversing mammary tumor-driven reprogramming of myelopoiesis to reduce metastatic spread. Cancer Cell 43, 1279–1295 (2025).
Google Scholar
Daman, A. W. et al. Microbial cancer immunotherapy reprograms hematopoiesis to enhance myeloid-driven anti-tumor immunity. Cancer Cell https://doi.org/10.1016/j.ccell.2025.05.002 (2025).
Google Scholar
Singh, A. et al. NRF2 activation promotes aggressive lung cancer and associates with poor clinical outcomes. Clin. Cancer Res. 27, 877–888 (2021).
Google Scholar
Chirnomas, D., Hornberger, K. R. & Crews, C. M. Protein degraders enter the clinic—a new approach to cancer therapy. Nat. Rev. Clin. Oncol. 20, 265–278 (2023).
Google Scholar
Mohamed, E. et al. The unfolded protein response mediator PERK governs myeloid cell-driven immunosuppression in tumors through inhibition of STING signaling. Immunity 52, 668–682 (2020).
Google Scholar
Raines, L. N. et al. PERK is a critical metabolic hub for immunosuppressive function in macrophages. Nat. Immunol. 23, 431–445 (2022).
Google Scholar
Kress, J. K. C. et al. The integrated stress response effector ATF4 is an obligatory metabolic activator of NRF2. Cell Rep. 42, 112724 (2023).
Google Scholar
Boumelha, J. et al. An immunogenic model of KRAS-mutant lung cancer enables evaluation of targeted therapy and immunotherapy combinations. Cancer Res. 82, 3435–3448 (2022).
Google Scholar
Jackson, E. L. et al. The differential effects of mutant p53 alleles on advanced murine lung cancer. Cancer Res. 65, 10280–10288 (2005).
Google Scholar
Bankhead, P. et al. QuPath: open source software for digital pathology image analysis. Sci. Rep. 7, 16878 (2017).
Google Scholar
Hao, Y. et al. Integrated analysis of multimodal single-cell data. Cell 184, 3573–3587 (2021).
Google Scholar
Martin, J. C. et al. Single-cell analysis of Crohn’s disease lesions identifies a pathogenic cellular module associated with resistance to anti-TNF therapy. Cell 178, 1493–1508 (2019).
Google Scholar
Andreatta, M. & Carmona, S. J. UCell: robust and scalable single-cell gene signature scoring. Comput. Struct. Biotechnol. J. 19, 3796–3798 (2021).
Google Scholar
Calcagno, D. M. et al. The myeloid type I interferon response to myocardial infarction begins in bone marrow and is regulated by Nrf2-activated macrophages. Sci. Immunol. 5, eaaz1974 (2020).
Google Scholar
Agrawal, A. et al. WikiPathways 2024: next generation pathway database. Nucleic Acids Res. 52, D679–D689 (2024).
Google Scholar
Crowell, H. L. et al. muscat detects subpopulation-specific state transitions from multi-sample multi-condition single-cell transcriptomics data. Nat. Commun. 11, 6077 (2020).
Google Scholar
Granja, J. M. et al. ArchR is a scalable software package for integrative single-cell chromatin accessibility analysis. Nat. Genet. 53, 403–411 (2021).
Google Scholar
Zhang, Y. et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 9, R137 (2008).
Google Scholar
Schep, A. N., Wu, B., Buenrostro, J. D. & Greenleaf, W. J. chromVAR: inferring transcription-factor-associated accessibility from single-cell epigenomic data. Nat. Methods 14, 975–978 (2017).
Google Scholar
Yoshida, H. et al. The cis-regulatory atlas of the mouse immune system. Cell 176, 897–912 (2019).
Google Scholar
McLean, C. Y. et al. GREAT improves functional interpretation of cis-regulatory regions. Nat. Biotechnol. 28, 495–501 (2010).
Google Scholar
Ma, S. et al. Chromatin potential identified by shared single-cell profiling of RNA and chromatin. Cell 183, 1103–1116 (2020).
Google Scholar
Kartha, V. K. et al. Functional inference of gene regulation using single-cell multi-omics. Cell Genom. 2, 100166 (2022).
Google Scholar
Lee, J. J. Early transcriptional effects of inflammatory cytokines reveal highly redundant cytokine networks. J. Exp. Med. 222, e20241207 (2025).
Google Scholar
Chen, Y. et al. Spatiotemporal single-cell analysis decodes cellular dynamics underlying different responses to immunotherapy in colorectal cancer. Cancer Cell 42, 1268–1285 (2024).
Google Scholar
Bassez, A. et al. A single-cell map of intratumoral changes during anti-PD1 treatment of patients with breast cancer. Nat. Med. 27, 820–832 (2021).
Google Scholar
Wolf, F. A., Angerer, P. & Theis, F. J. SCANPY: large-scale single-cell gene expression data analysis. Genome Biol. 19, 15 (2018).
Google Scholar
Gayoso, A. et al. A Python library for probabilistic analysis of single-cell omics data. Nat. Biotechnol. 40, 163–166 (2022).
Google Scholar
Bravo Gonzalez-Blas, C. et al. SCENIC+: single-cell multiomic inference of enhancers and gene regulatory networks. Nat. Methods 20, 1355–1367 (2023).
Google Scholar
McDavid, A. et al. Data exploration, quality control and testing in single-cell qPCR-based gene expression experiments. Bioinformatics 29, 461–467 (2013).
Google Scholar