DeNardo, D. G. & Ruffell, B. Macrophages as regulators of tumour immunity and immunotherapy. Nat. Rev. Immunol. 19, 369–382 (2019).
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).
Goswami, S., Anandhan, S., Raychaudhuri, D. & Sharma, P. Myeloid cell-targeted therapies for solid tumours. Nat. Rev. Immunol. 23, 106–120 (2023).
Sica, A., Guarneri, V. & Gennari, A. Myelopoiesis, metabolism and therapy: a crucial crossroads in cancer progression. Cell Stress 3, 284–294 (2019).
Giles, A. J. et al. Activation of hematopoietic stem/progenitor cells promotes immunosuppression within the pre-metastatic niche. Cancer Res. 76, 1335–1347 (2016).
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).
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).
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).
Trzebanski, S. et al. Classical monocyte ontogeny dictates their functions and fates as tissue macrophages. Immunity 57, 1225–1243 (2024).
Ikeda, N. et al. The early neutrophil-committed progenitors aberrantly differentiate into immunoregulatory monocytes during emergency myelopoiesis. Cell Rep. 42, 112165 (2023).
LaMarche, N. M. et al. An IL-4 signalling axis in bone marrow drives pro-tumorigenic myelopoiesis. Nature 625, 166–174 (2024).
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).
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).
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).
Pham, T. H. et al. Dynamic epigenetic enhancer signatures reveal key transcription factors associated with monocytic differentiation states. Blood 119, e161–e171 (2012).
Mandula, J. K. & Rodriguez, P. C. Tumor-related stress regulates functional plasticity of MDSCs. Cell Immunol. 363, 104312 (2021).
Paul, F. et al. Transcriptional heterogeneity and lineage commitment in myeloid progenitors. Cell 163, 1663–1677 (2015).
Kwart, D. et al. Cancer cell-derived type I interferons instruct tumor monocyte polarization. Cell Rep. 41, 111769 (2022).
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).
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).
Pizzato, H. A. et al. Mitochondrial pyruvate metabolism and glutaminolysis toggle steady-state and emergency myelopoiesis. J. Exp. Med. 220, e20221373 (2023).
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).
Molgora, M. et al. TREM2 modulation remodels the tumor myeloid landscape enhancing anti-PD-1 immunotherapy. Cell 182, 886–900 (2020).
Katzenelenbogen, Y. et al. Coupled scRNA-seq and intracellular protein activity reveal an immunosuppressive role of TREM2 in cancer. Cell 182, 872–885 (2020).
Matusiak, M. et al. Spatially segregated macrophage populations predict distinct outcomes in colon cancer. Cancer Discov. 14, 1418–1439 (2024).
Mulder, K. et al. Cross-tissue single-cell landscape of human monocytes and macrophages in health and disease. Immunity 54, 1883–1900 (2021).
McGinnis, C. S. et al. The temporal progression of lung immune remodeling during breast cancer metastasis. Cancer Cell 42, 1018–1031 (2024).
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).
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).
Kobayashi, E. H. et al. Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription. Nat. Commun. 7, 11624 (2016).
Ryan, D. G. et al. Nrf2 activation reprograms macrophage intermediary metabolism and suppresses the type I interferon response. iScience 25, 103827 (2022).
Olagnier, D. et al. Nrf2 negatively regulates STING indicating a link between antiviral sensing and metabolic reprogramming. Nat. Commun. 9, 3506 (2018).
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).
Park, M. D. et al. TREM2 macrophages drive NK cell paucity and dysfunction in lung cancer. Nat. Immunol. 24, 792–801 (2023).
Alaluf, E. et al. Heme oxygenase-1 orchestrates the immunosuppressive program of tumor-associated macrophages. JCI Insight 5, e133929 (2020).
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).
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).
Zelenay, S. et al. Cyclooxygenase-dependent tumor growth through evasion of immunity. Cell 162, 1257–1270 (2015).
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).
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).
Li, Z. et al. Proinflammatory S100A8 induces PD-L1 expression in macrophages, mediating tumor immune escape. J. Immunol. 204, 2589–2599 (2020).
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).
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).
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).
Liu, Z. et al. Fate mapping via Ms4a3-expression history traces monocyte-derived cells. Cell 178, 1509–1525 (2019).
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).
Perrone, M. et al. ATF3 reprograms the bone marrow niche in response to early breast cancer transformation. Cancer Res. 83, 117–129 (2023).
Zhang, M. et al. Selective activation of STAT3 and STAT5 dictates the fate of myeloid progenitor cells. Cell Death Discov. 9, 274 (2023).
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).
Villar, J. et al. ETV3 and ETV6 enable monocyte differentiation into dendritic cells by repressing macrophage fate commitment. Nat. Immunol. 24, 84–95 (2023).
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).
Ng, M. S. F. et al. Deterministic reprogramming of neutrophils within tumors. Science 383, eadf6493 (2024).
Zhao, Y. et al. Neutrophils resist ferroptosis and promote breast cancer metastasis through aconitate decarboxylase 1. Cell Metab. 35, 1688–1703 (2023).
Garner, H. et al. Understanding and reversing mammary tumor-driven reprogramming of myelopoiesis to reduce metastatic spread. Cancer Cell 43, 1279–1295 (2025).
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).
Singh, A. et al. NRF2 activation promotes aggressive lung cancer and associates with poor clinical outcomes. Clin. Cancer Res. 27, 877–888 (2021).
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).
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).
Raines, L. N. et al. PERK is a critical metabolic hub for immunosuppressive function in macrophages. Nat. Immunol. 23, 431–445 (2022).
Kress, J. K. C. et al. The integrated stress response effector ATF4 is an obligatory metabolic activator of NRF2. Cell Rep. 42, 112724 (2023).
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).
Jackson, E. L. et al. The differential effects of mutant p53 alleles on advanced murine lung cancer. Cancer Res. 65, 10280–10288 (2005).
Bankhead, P. et al. QuPath: open source software for digital pathology image analysis. Sci. Rep. 7, 16878 (2017).
Hao, Y. et al. Integrated analysis of multimodal single-cell data. Cell 184, 3573–3587 (2021).
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).
Andreatta, M. & Carmona, S. J. UCell: robust and scalable single-cell gene signature scoring. Comput. Struct. Biotechnol. J. 19, 3796–3798 (2021).
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).
Agrawal, A. et al. WikiPathways 2024: next generation pathway database. Nucleic Acids Res. 52, D679–D689 (2024).
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).
Granja, J. M. et al. ArchR is a scalable software package for integrative single-cell chromatin accessibility analysis. Nat. Genet. 53, 403–411 (2021).
Zhang, Y. et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 9, R137 (2008).
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).
Yoshida, H. et al. The cis-regulatory atlas of the mouse immune system. Cell 176, 897–912 (2019).
McLean, C. Y. et al. GREAT improves functional interpretation of cis-regulatory regions. Nat. Biotechnol. 28, 495–501 (2010).
Ma, S. et al. Chromatin potential identified by shared single-cell profiling of RNA and chromatin. Cell 183, 1103–1116 (2020).
Kartha, V. K. et al. Functional inference of gene regulation using single-cell multi-omics. Cell Genom. 2, 100166 (2022).
Lee, J. J. Early transcriptional effects of inflammatory cytokines reveal highly redundant cytokine networks. J. Exp. Med. 222, e20241207 (2025).
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).
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).
Wolf, F. A., Angerer, P. & Theis, F. J. SCANPY: large-scale single-cell gene expression data analysis. Genome Biol. 19, 15 (2018).
Gayoso, A. et al. A Python library for probabilistic analysis of single-cell omics data. Nat. Biotechnol. 40, 163–166 (2022).
Bravo Gonzalez-Blas, C. et al. SCENIC+: single-cell multiomic inference of enhancers and gene regulatory networks. Nat. Methods 20, 1355–1367 (2023).
McDavid, A. et al. Data exploration, quality control and testing in single-cell qPCR-based gene expression experiments. Bioinformatics 29, 461–467 (2013).