Swanton, C. et al. Embracing cancer complexity: hallmarks of systemic disease. Cell 187, 1589–1616 (2024).
Lim, S. A. Metabolic reprogramming of the tumor microenvironment to enhance immunotherapy. BMB Rep. 57, 388–399 (2024).
Baghban, R. et al. Tumor microenvironment complexity and therapeutic implications at a glance. Cell Commun Signal 18, 59 (2020).
Poyia, F., Neophytou, C. M., Christodoulou, M. I. & Papageorgis, P. The role of tumor microenvironment in pancreatic cancer immunotherapy: current status and future perspectives. Int. J. Mol. Sci. (2024).
Basak, U. et al. Tumor-associated macrophages: an effective player of the tumor microenvironment. Front. Immunol. 14, 1295257 (2023).
Pan, Y. et al. Regulatory T cells in solid tumor immunotherapy: effect, mechanism and clinical application. Cell Death Dis 16, 277 (2025).
Li, K. et al. Myeloid-derived suppressor cells as immunosuppressive regulators and therapeutic targets in cancer. Signal Transduct. Target. Ther. 6, 362 (2021).
Lu, J. et al. Myeloid-derived suppressor cells in cancer: therapeutic targets to overcome tumor immune evasion. Exp. Hematol. Oncol. 13, 39 (2024).
Arner, E. N. & Rathmell, J. C. Metabolic programming and immune suppression in the tumor microenvironment. Cancer Cell 41, 421–433 (2023).
Yan, Y. et al. Metabolic profiles of regulatory T cells and their adaptations to the tumor microenvironment: implications for antitumor immunity. J. Hematol. Oncol. 15, 104 (2022).
Goldmann, O. & Medina, E. Metabolic pathways fueling the suppressive activity of myeloid-derived suppressor cells. Front. Immunol. 15, 1461455 (2024).
Qian, Y., Yin, Y., Zheng, X., Liu, Z. & Wang, X. Metabolic regulation of tumor-associated macrophage heterogeneity: insights into the tumor microenvironment and immunotherapeutic opportunities. Biomark. Res. 12, 1 (2024).
Lv, Y. et al. Metabolic checkpoints in immune cell reprogramming: rewiring immunometabolism for cancer therapy. Mol. Cancer 24, 210 (2025).
Zhang, Z. et al. Immunometabolism in the tumor microenvironment and its related research progress. Front. Oncol. 12, 1024789 (2022).
Gabrilovich, D. I. & Nagaraj, S. Myeloid-derived suppressor cells as regulators of the immune system. Nat. Rev. Immunol. 9, 162–174 (2009).
Kumar, V., Patel, S., Tcyganov, E. & Gabrilovich, D. I. The nature of myeloid-derived suppressor cells in the tumor microenvironment. Trends Immunol. 37, 208–220 (2016).
Wu, Y., Yi, M., Niu, M., Mei, Q. & Wu, K. Myeloid-derived suppressor cells: an emerging target for anticancer immunotherapy. Mol. Cancer 21, 184 (2022).
Veglia, F., Perego, M. & Gabrilovich, D. Myeloid-derived suppressor cells coming of age. Nat. Immunol. 19, 108–119 (2018).
Noy, R. & Pollard, J. W. Tumor-associated macrophages: from mechanisms to therapy. Immunity 41, 49–61 (2014).
Zhang, X. M., Chen, D. G., Li, S. C., Zhu, B. & Li, Z. J. Embryonic origin and subclonal evolution of tumor-associated macrophages imply preventive care for cancer. Cells (2021).
Movahedi, K. et al. Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes. Cancer Res. 70, 5728–5739 (2010).
Laviron, M. & Boissonnas, A. Ontogeny of tumor-associated macrophages. Front. Immunol. 10, 1799 (2019).
Saeed, A. F. Tumor-associated macrophages: polarization, immunoregulation, and immunotherapy. Cells (2025).
de Groot, A. E. et al. Targeting interleukin 4 receptor alpha on tumor-associated macrophages reduces the pro-tumor macrophage phenotype. Neoplasia 32, 100830 (2022).
Gao, J., Liang, Y. & Wang, L. Shaping polarization of tumor-associated macrophages in cancer immunotherapy. Front. Immunol. 13, 888713 (2022).
Masucci, M. T., Minopoli, M. & Carriero, M. V. Tumor associated neutrophils. their role in tumorigenesis, metastasis, prognosis and therapy. Front. Oncol. 9, 1146 (2019).
Fridlender, Z. G. et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Cancer Cell 16, 183–194 (2009).
Yang, M. et al. Tumour-associated neutrophils orchestrate intratumoural IL-8-driven immune evasion through Jagged2 activation in ovarian cancer. Br. J. Cancer 123, 1404–1416 (2020).
Huang, S., Shi, J., Shen, J. & Fan, X. Metabolic reprogramming of neutrophils in the tumor microenvironment: emerging therapeutic targets. Cancer Lett. 612, 217466 (2025).
Togashi, Y., Shitara, K. & Nishikawa, H. Regulatory T cells in cancer immunosuppression — implications for anticancer therapy. Nat. Rev. Clin. Oncol. 16, 356–371 (2019).
Lehtimaki, S. & Lahesmaa, R. Regulatory T cells control immune responses through their non-redundant tissue specific features. Front. Immunol. 4, 294 (2013).
Schmitt, E. G. & Williams, C. B. Generation and function of induced regulatory T cells. Front. Immunol. 4, 152 (2013).
Wan, Y. Y. Regulatory T cells: immune suppression and beyond. Cell Mol. Immunol. 7, 204–210 (2010).
Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057–1061 (2003).
Dikiy, S. et al. A distal Foxp3 enhancer enables interleukin-2 dependent thymic Treg cell lineage commitment for robust immune tolerance. Immunity 54, 931–946 e911 (2021).
Zheng, Y. et al. Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature 463, 808–812 (2010).
Kim, J., Li, J., Wei, J. & Lim, S. A. Regulatory T cell metabolism: a promising therapeutic target for cancer treatment?. Immune Netw. 25, e13 (2025).
Iglesias-Escudero, M., Arias-Gonzalez, N. & Martinez-Caceres, E. Regulatory cells and the effect of cancer immunotherapy. Mol. Cancer 22, 26 (2023).
Li, J. et al. PD-1+ mast cell enhanced by PD-1 blocking therapy associated with resistance to immunotherapy. Cancer Immunol. Immunother. 72, 633–645 (2023).
Oldford, S. A. & Marshall, J. S. Mast cells as targets for immunotherapy of solid tumors. Mol. Immunol. 63, 113–124 (2015).
Murakami, Y. et al. Increased regulatory B cells are involved in immune evasion in patients with gastric cancer. Sci Rep 9, 13083 (2019).
Zacca, E. R. et al. PD-L1+ regulatory B cells are significantly decreased in rheumatoid arthritis patients and increase after successful treatment. Front. Immunol. 9, 2241 (2018).
Wu, H. et al. PD-L1+ regulatory B cells act as a T cell suppressor in a PD-L1-dependent manner in melanoma patients with bone metastasis. Mol. Immunol. 119, 83–91 (2020).
Xiu, W., Ma, J., Lei, T., Zhang, M. & Zhou, S. Immunosuppressive effect of bladder cancer on function of dendritic cells involving of Jak2/STAT3 pathway. Oncotarget 7, 63204–63214 (2016).
Sage, P. T. et al. Dendritic cell PD-L1 limits autoimmunity and follicular T cell differentiation and function. J. Immunol. 200, 2592–2602 (2018).
Peng, Q. et al. PD-L1 on dendritic cells attenuates T cell activation and regulates response to immune checkpoint blockade. Nat. Commun. 11, 4835 (2020).
Corzo, C. A. et al. HIF-1alpha regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J. Exp. Med. 207, 2439–2453 (2010).
Chiu, D. K. et al. Hypoxia induces myeloid-derived suppressor cell recruitment to hepatocellular carcinoma through chemokine (C-C motif) ligand 26. Hepatology 64, 797–813 (2016).
Chiu, D. K. et al. Hypoxia inducible factor HIF-1 promotes myeloid-derived suppressor cells accumulation through ENTPD2/CD39L1 in hepatocellular carcinoma. Nat. Commun. 8, 517 (2017).
Al-Khami, A. A. et al. Exogenous lipid uptake induces metabolic and functional reprogramming of tumor-associated myeloid-derived suppressor cells. Oncoimmunology 6, e1344804 (2017).
Hossain, F. et al. Inhibition of fatty acid oxidation modulates immunosuppressive functions of myeloid-derived suppressor cells and enhances cancer therapies. Cancer Immunol. Res. 3, 1236–1247 (2015).
Zhao, J. L. et al. Notch-mediated lactate metabolism regulates MDSC development through the Hes1/MCT2/c-Jun axis. Cell Rep. 38, 110451 (2022).
Yang, X. et al. Lactate-modulated immunosuppression of myeloid-derived suppressor cells contributes to the radioresistance of pancreatic cancer. Cancer Immunol. Res. 8, 1440–1451 (2020).
Yang, Y., Li, C., Liu, T., Dai, X. & Bazhin, A. V. Myeloid-derived suppressor cells in tumors: from mechanisms to antigen specificity and microenvironmental regulation. Front. Immunol. 11, 1371 (2020).
Carmona-Fontaine, C. et al. Metabolic origins of spatial organization in the tumor microenvironment. Proc. Natl Acad. Sci. USA 114, 2934–2939 (2017).
Colegio, O. R. et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513, 559–563 (2014).
Su, P. et al. Enhanced lipid accumulation and metabolism are required for the differentiation and activation of tumor-associated macrophages. Cancer Res. 80, 1438–1450 (2020).
Szanto, A. et al. STAT6 transcription factor is a facilitator of the nuclear receptor PPARgamma-regulated gene expression in macrophages and dendritic cells. Immunity 33, 699–712 (2010).
Hinshaw, D. C. et al. Hedgehog signaling regulates metabolism and polarization of mammary tumor-associated macrophages. Cancer Res 81, 5425–5437 (2021).
Zhao, Y. et al. Macrophage transcriptome modification induced by hypoxia and lactate. Exp Ther Med 18, 4811–4819 (2019).
Zhou, H. et al. Lactate-induced CCL8 in tumor-associated macrophages accelerates the progression of colorectal cancer through the CCL8/CCR5/mTORC1 axis. Cancers (2023).
Tohme, S. et al. Neutrophil extracellular traps promote the development and progression of liver metastases after surgical stress. Cancer Res. 76, 1367–1380 (2016).
Yang, S. et al. Neutrophil extracellular traps promote angiogenesis in gastric cancer. Cell Commun. Signal 21, 176 (2023).
Tadie, J. M. et al. HMGB1 promotes neutrophil extracellular trap formation through interactions with Toll-like receptor 4. Am. J. Physiol. Lung Cell Mol. Physiol. 304, L342–349 (2013).
Mahiddine, K. et al. Relief of tumor hypoxia unleashes the tumoricidal potential of neutrophils. J. Clin. Invest. 130, 389–403 (2020).
Zhao, Y. et al. Neutrophils resist ferroptosis and promote breast cancer metastasis through aconitate decarboxylase 1. Cell Metab 35, 1688–1703 (2023).
Li, P. et al. Lung mesenchymal cells elicit lipid storage in neutrophils that fuel breast cancer lung metastasis. Nat. Immunol. 21, 1444–1455 (2020).
Yu, L. et al. Tumor-derived arachidonic acid reprograms neutrophils to promote immune suppression and therapy resistance in triple-negative breast cancer. Immunity 58, 909–925 (2025).
Clambey, E. T. et al. Hypoxia-inducible factor-1 alpha-dependent induction of FoxP3 drives regulatory T-cell abundance and function during inflammatory hypoxia of the mucosa. Proc. Natl Acad. Sci. USA 109, E2784–2793 (2012).
Westendorf, A. M. et al. Hypoxia Enhances Immunosuppression by Inhibiting CD4+ effector T cell function and promoting Treg activity. Cell Physiol. Biochem. 41, 1271–1284 (2017).
Mayer, A., Schneider, F., Vaupel, P., Sommer, C. & Schmidberger, H. Differential expression of HIF-1 in glioblastoma multiforme and anaplastic astrocytoma. Int. J. Oncol. 41, 1260–1270 (2012).
Dang, E. V. et al. Control of TH17/Treg balance by hypoxia-inducible factor 1. Cell 146, 772–784 (2011).
Michalek, R. D. et al. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J. Immunol. 186, 3299–3303 (2011).
Miska, J. et al. HIF-1alpha is a metabolic switch between glycolytic-driven migration and oxidative phosphorylation-driven immunosuppression of tregs in glioblastoma. Cell Rep 27, 226–237 (2019).
Hsu, T. S. et al. HIF-2alpha is indispensable for regulatory T cell function. Nat. Commun. 11, 5005 (2020).
Multhoff, G. & Vaupel, P. Lactate-avid regulatory T cells: metabolic plasticity controls immunosuppression in tumour microenvironment. Signal Transduct. Target. Ther. 6, 171 (2021).
Watson, M. J. et al. Metabolic support of tumour-infiltrating regulatory T cells by lactic acid. Nature 591, 645–651 (2021).
Ding, R. et al. Lactate modulates RNA splicing to promote CTLA-4 expression in tumor-infiltrating regulatory T cells. Immunity 57, 528–540 (2024).
Zhang, Y. et al. Lactate acid promotes PD-1+ Tregs accumulation in the bone marrow with high tumor burden of Acute myeloid leukemia. Int Immunopharmacol 130, 111765 (2024).
Feng, Q. et al. Lactate increases stemness of CD8+ T cells to augment anti-tumor immunity. Nat. Commun. 13, 4981 (2022).
Lieu, E. L., Nguyen, T., Rhyne, S. & Kim, J. Amino acids in cancer. Exp. Mol. Med. 52, 15–30 (2020).
Cobbold, S. P. et al. Infectious tolerance via the consumption of essential amino acids and mTOR signaling. Proc. Natl Acad. Sci. USA 106, 12055–12060 (2009).
Seo, S. K. & Kwon, B. Immune regulation through tryptophan metabolism. Exp. Mol. Med. 55, 1371–1379 (2023).
Long, Y. et al. Dysregulation of glutamate transport enhances Treg function that promotes VEGF blockade resistance in glioblastoma. Cancer Res. 80, 499–509 (2020).
Aboelella, N. S., Brandle, C., Kim, T., Ding, Z. C. & Zhou, G. Oxidative stress in the tumor microenvironment and its relevance to cancer immunotherapy. Cancers (2021).
Maj, T. et al. Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor. Nat. Immunol. 18, 1332–1341 (2017).
Cheng, W. C. & Ho, P. C. Metabolic tug-of-war in tumors results in diminished T cell antitumor immunity. Oncoimmunology 5, e1119355 (2016).
Chang, C. H. et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162, 1229–1241 (2015).
Rodriguez, P. C. & Ochoa, A. C. Arginine regulation by myeloid derived suppressor cells and tolerance in cancer: mechanisms and therapeutic perspectives. Immunol. Rev. 222, 180–191 (2008).
Munn, D. H. & Mellor, A. L. Indoleamine 2,3 dioxygenase and metabolic control of immune responses. Trends Immunol. 34, 137–143 (2013).
Leone, R. D. et al. Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion. Science 366, 1013–1021 (2019).
Brand, A. et al. LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab. 24, 657–671 (2016).
Quinn, W. J. 3rd et al. Lactate limits T cell proliferation via the NAD(H) redox state. Cell Rep. 33, 108500 (2020).
Deaglio, S. et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J. Exp. Med. 204, 1257–1265 (2007).
Sorrentino, C. et al. Adenosine A2A receptor stimulation inhibits TCR-induced Notch1 activation in CD8+ T-cells. Front. Immunol. 10, 162 (2019).
Pearce, E. L., Poffenberger, M. C., Chang, C. H. & Jones, R. G. Fueling immunity: insights into metabolism and lymphocyte function. Science 342, 1242454 (2013).
Frauwirth, K. A. et al. The CD28 signaling pathway regulates glucose metabolism. Immunity 16, 769–777 (2002).
Wofford, J. A., Wieman, H. L., Jacobs, S. R., Zhao, Y. & Rathmell, J. C. IL-7 promotes Glut1 trafficking and glucose uptake via STAT5-mediated activation of Akt to support T-cell survival. Blood 111, 2101–2111 (2008).
Parry, R. V. et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol. Cell Biol. 25, 9543–9553 (2005).
Hui, E. et al. T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science 355, 1428–1433 (2017).
Geiger, R. et al. L-Arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell 167, 829–842 (2016).
Adeshakin, A. O. et al. Regulation of ROS in myeloid-derived suppressor cells through targeting fatty acid transport protein 2 enhanced anti-PD-L1 tumor immunotherapy. Cell Immunol. 362, 104286 (2021).
Steggerda, S. M. et al. Inhibition of arginase by CB-1158 blocks myeloid cell-mediated immune suppression in the tumor microenvironment. J. Immunother. Cancer 5, 101 (2017).
Naing, A. et al. First-in-human phase 1 study of the arginase inhibitor INCB001158 alone or combined with pembrolizumab in patients with advanced or metastatic solid tumours. BMJ Oncol. 3, e000249 (2024).
Deng, Y. T. et al. mTOR-mediated glycolysis contributes to the enhanced suppressive function of murine tumor-infiltrating monocytic myeloid-derived suppressor cells. Cancer Immunol. Immun. 67, 1355–1364 (2018).
Li, Z. et al. SLC3A2 promotes tumor-associated macrophage polarization through metabolic reprogramming in lung cancer. Cancer Sci. 114, 2306–2317 (2023).
Palmieri, E. M. et al. Pharmacologic or genetic targeting of glutamine synthetase skews macrophages toward an M1-like phenotype and inhibits tumor metastasis. Cell Rep. 20, 1654–1666 (2017).
Chen, P. et al. Gpr132 sensing of lactate mediates tumor-macrophage interplay to promote breast cancer metastasis. Proc. Natl Acad. Sci. USA 114, 580–585 (2017).
Zhao, Q. et al. 2-Deoxy-d-glucose treatment decreases anti-inflammatory M2 macrophage polarization in mice with tumor and allergic airway inflammation. Front. Immunol. 8, 637 (2017).
Liu, P. S. et al. CD40 signal rewires fatty acid and glutamine metabolism for stimulating macrophage anti-tumorigenic functions. Nat. Immunol. 24, 452–462 (2023).
DeNardo, D. G. & Ruffell, B. Macrophages as regulators of tumour immunity and immunotherapy. Nat. Rev. Immunol. 19, 369–382 (2019).
Kim, R. et al. Ferroptosis of tumour neutrophils causes immune suppression in cancer. Nature 612, 338–346 (2022).
Veglia, F. et al. Fatty acid transport protein 2 reprograms neutrophils in cancer. Nature 569, 73–78 (2019).
Hu, C., Pang, B., Lin, G., Zhen, Y. & Yi, H. Energy metabolism manipulates the fate and function of tumour myeloid-derived suppressor cells. Br. J. Cancer 122, 23–29 (2020).
Sun, H. W. et al. Retinoic acid synthesis deficiency fosters the generation of polymorphonuclear myeloid-derived suppressor cells in colorectal cancer. Cancer Immunol. Res. 9, 20–33 (2021).
Ding, X., Zhao, T., Lee, C. C., Yan, C. & Du, H. Lysosomal acid lipase deficiency controls T- and B-regulatory cell homeostasis in the lymph nodes of mice with human cancer xenotransplants. Am. J. Pathol. 191, 353–367 (2021).
Xu, R. et al. Glucose metabolism characteristics and TLR8-mediated metabolic control of CD4+ Treg cells in ovarian cancer cells microenvironment. Cell Death Dis. 12, 22 (2021).
Ge, S. et al. Discovery of secondary sulphonamides as IDO1 inhibitors with potent antitumour effects in vivo. J Enzyme Inhib Med Chem 35, 1240–1257 (2020).
Ota, Y. et al. DSP-0509, a TLR7 agonist, exerted synergistic anti-tumor immunity combined with various immune therapies through modulating diverse immune cells in cancer microenvironment. Front. Oncol. 14, 1410373 (2024).
Long, G. V. et al. Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomised, double-blind study. Lancet Oncol. 20, 1083–1097 (2019).
Pacella, I. et al. Fatty acid metabolism complements glycolysis in the selective regulatory T cell expansion during tumor growth. Proc. Natl Acad. Sci. USA 115, E6546–E6555 (2018).
O’Connor, R. S. et al. The CPT1a inhibitor, etomoxir induces severe oxidative stress at commonly used concentrations. Sci. Rep. 8, 6289 (2018).
Raud, B. et al. Etomoxir actions on regulatory and memory T cells are independent of Cpt1a-mediated fatty acid oxidation. Cell Metab 28, 504–515 e507 (2018).
Wang, H. et al. CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors. Nat. Immunol. 21, 298–308 (2020).
Adeshakin, A. O. et al. Lipidomics data showing the effect of lipofermata on myeloid-derived suppressor cells in the spleens of tumor-bearing mice. Data Brief. 35, 106882 (2021).
Steggerda, S. M. et al. Inhibition of arginase by CB-1158 blocks myeloid cell-mediated immune suppression in the tumor microenvironment. J. Immunother. Cancer (2017).