Myeloid cells: key players in tumor microenvironments

Abstract

Cancer is the result of evolving crosstalk between neoplastic cell and its immune microenvironment. In recent years, immune therapeutics targeting T lymphocytes, such as immune checkpoint blockade (ICB) and CAR-T, have made significant progress in cancer treatment and validated targeting immune cells as a promising approach to fight human cancers. However, responsiveness to the current immune therapeutic agents is limited to only a small proportion of solid cancer patients. As major components of most solid tumors, myeloid cells played critical roles in regulating the initiation and sustentation of adaptive immunity, thus determining tumor progression as well as therapeutic responses. In this review, we discuss emerging data on the diverse functions of myeloid cells in tumor progression through their direct effects or interactions with other immune cells. We explain how different metabolic reprogramming impacts the characteristics and functions of tumor myeloid cells, and discuss recent progress in revealing different mechanisms—chemotaxis, proliferation, survival, and alternative sources—involved in the infiltration and accumulation of myeloid cells within tumors. Further understanding of the function and regulation of myeloid cells is important for the development of novel strategies for therapeutic exploitation in cancer.

Keywords

myeloid cells / ICB treatment / immune therapy / tumor microenvironments

References

[1] de Visser KE, Joyce JA. The evolving tumor microenvironment from cancer initiation to metastatic outgrowth. Cancer Cell 2023; 41(3): 374–403

[2] Mellman I, Chen DS, Powles T, Turley SJ. The cancer-immunity cycle: indication, genotype, and immunotype. Immunity 2023; 56(10): 2188–2205

[3] Kubli SP, Berger T, Araujo DV, Siu LL, Mak TW. Beyond immune checkpoint blockade: emerging immunological strategies. Nat Rev Drug Discov 2021; 20(12): 899–919

[4] Morad G, Helmink BA, Sharma P, Wargo JA. Hallmarks of response, resistance, and toxicity to immune checkpoint blockade. Cell 2022; 185(3): 576

[5] Topalian SL, Forde PM, Emens LA, Yarchoan M, Smith KN, Pardoll DM. Neoadjuvant immune checkpoint blockade: a window of opportunity to advance cancer immunotherapy. Cancer Cell 2023; 41(9): 1551–1566

[6] Cassetta L, Pollard JW. Targeting macrophages: therapeutic approaches in cancer. Nat Rev Drug Discov 2018; 17(12): 887–904

[7] Engblom C, Pfirschke C, Pittet MJ. The role of myeloid cells in cancer therapies. Nat Rev Cancer 2016; 16(7): 447–462

[8] Mantovani A, Marchesi F, Jaillon S, Garlanda C, Allavena P. Tumor-associated myeloid cells: diversity and therapeutic targeting. Cell Mol Immunol 2021; 18(3): 566–578

[9] Veglia F, Sanseviero E, Gabrilovich DI. Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity. Nat Rev Immunol 2021; 21(8): 485–498

[10] Cheng J, Huo DH, Kuang DM, Yang J, Zheng L, Zhuang SM. Human macrophages promote the motility and invasiveness of osteopontin-knockdown tumor cells. Cancer Res 2007; 67(11): 5141–5147

[11] Mantovani A, Garlanda C. Humoral innate immunity and acute-phase proteins. N Engl J Med 2023; 388(5): 439–452

[12] Mantovani A, Allavena P, Marchesi F, Garlanda C. Macrophages as tools and targets in cancer therapy. Nat Rev Drug Discov 2022; 21(11): 799–820

[13] van Vlerken-Ysla L, Tyurina YY, Kagan VE, Gabrilovich DI. Functional states of myeloid cells in cancer. Cancer Cell 2023; 41(3): 490–504

[14] Barry ST, Gabrilovich DI, Sansom OJ, Campbell AD, Morton JP. Therapeutic targeting of tumour myeloid cells. Nat Rev Cancer 2023; 23(4): 216–237

[15] Goswami S, Anandhan S, Raychaudhuri D, Sharma P. Myeloid cell-targeted therapies for solid tumours. Nat Rev Immunol 2023; 23(2): 106–120

[16] Chen S, Saeed AFUH, Liu Q, Jiang Q, Xu H, Xiao GG, Rao L, Duo Y. Macrophages in immunoregulation and therapeutics. Signal Transduct Target Ther 2023; 8(1): 207–1

[17] Lazarov T, Juarez-Carreño S, Cox N, Geissmann F. Publisher correction: physiology and diseases of tissue-resident macrophages. Nature 2023; 619(7970): E51

[18] Guilliams M, Mildner A, Yona S. Developmental and functional heterogeneity of monocytes. Immunity 2018; 49(4): 595–613

[19] Youn JI, Collazo M, Shalova IN, Biswas SK, Gabrilovich DI. Characterization of the nature of granulocytic myeloid-derived suppressor cells in tumor-bearing mice. J Leukoc Biol 2012; 91(1): 167–181

[20] Grover A, Sanseviero E, Timosenko E, Gabrilovich DI. Myeloid-derived suppressor cells: a propitious road to clinic. Cancer Discov 2021; 11(11): 2693–2706

[21] Tcyganov E, Mastio J, Chen E, Gabrilovich DI. Plasticity of myeloid-derived suppressor cells in cancer. Curr Opin Immunol 2018; 51: 76–82

[22] Xiang XN, Wang J, Lu D, Xu X. Targeting tumor-associated macrophages to synergize tumor immunotherapy. Signal Transduct Target Ther 2021; 6(1): 75

[23] Christofides A, Strauss L, Yeo A, Cao C, Charest A, Boussiotis VA. The complex role of tumor-infiltrating macrophages. Nat Immunol 2022; 23(8): 1148–1156

[24] Wang B, Xu D, Yu X, Ding T, Rao H, Zhan Y, Zheng L, Li L. Association of intra-tumoral infiltrating macrophages and regulatory T cells is an independent prognostic factor in gastric cancer after radical resection. Ann Surg Oncol 2011; 18(9): 2585–2593

[25] Li J, Ye Y, Liu Z, Zhang G, Dai H, Li J, Zhou B, Li Y, Zhao Q, Huang J, Feng J, Liu S, Ruan P, Wang J, Liu J, Huang M, Liu X, Yu S, Liang Z, Ma L, Gou X, Zhang G, Chen N, Lu Y, Di C, Xia Q, Pan J, Feng R, Cai Q, Su S. Macrophage mitochondrial fission improves cancer cell phagocytosis induced by therapeutic antibodies and is impaired by glutamine competition. Nat Can 2022; 3(4): 453–470

[26] Deng ZH, Loyher PL, Lazarov T, Li L, Shen Z, Bhinder B, Yang H, Zhong Y, Alberdi A, Massague J, Sun JC, Benezra R, Glass CK, Elemento O, Iacobuzio-Donahue CA, Geissmann F. The nuclear factor ID3 endows macrophages with a potent anti-tumour activity. Nature 2024; 626(8000): 864–873

[27] Goubet AG, Pittet MJ. Unveiling the antitumor function of ID3 in liver macrophages. Nat Immunol 2024; 25(3): 394–395

[28] Ding CL, Shrestha R, Zhu X, Geller AE, Wu S, Woeste MR, Li W, Wang H, Yuan F, Xu R, Chariker JH, Hu X, Li H, Tieri D, Zhang HG, Rouchka EC, Mitchell R, Siskind LJ, Zhang X, Xu XG, McMasters KM, Yu Y, Yan J. Inducing trained immunity in pro-metastatic macrophages to control tumor metastasis. Nat Immunol 2023; 24(2): 239–254

[29] Kuang DM, Wu Y, Chen N, Cheng J, Zhuang SM, Zheng L. Tumor-derived hyaluronan induces formation of immunosuppressive macrophages through transient early activation of monocytes. Blood 2007; 110(2): 587–595

[30] Bied M, Ho WW, Ginhoux F, Blériot C. Roles of macrophages in tumor development: a spatiotemporal perspective. Cell Mol Immunol 2023; 20(9): 983–992

[31] Rashidi A, Billingham LK, Zolp A, Chia T, Silvers C, Katz JL, Park CH, Delay S, Boland L, Geng Y, Markwell SM, Dmello C, Arrieta VA, Zilinger K, Jacob IM, Lopez-Rosas A, Hou D, Castro B, Steffens AM, McCortney K, Walshon JP, Flowers MS, Lin H, Wang H, Zhao J, Sonabend A, Zhang P, Ahmed AU, Brat DJ, Heiland DH, Lee-Chang C, Lesniak MS, Chandel NS, Miska J. Myeloid cell-derived creatine in the hypoxic niche promotes glioblastoma growth. Cell Metab 2024; 36(1): 62–77.e8

[32] Zhao L, Wu Y, Xie XD, Chu YF, Li JQ, Zheng L. c-Met identifies a population of matrix metalloproteinase 9-producing monocytes in peritumoural stroma of hepatocellular carcinoma. J Pathol 2015; 237(3): 319–329

[33] Shi QZ, Shen Q, Liu Y, Shi Y, Huang W, Wang X, Li Z, Chai Y, Wang H, Hu X, Li N, Zhang Q, Cao X. Increased glucose metabolism in TAMs fuels O-GlcNAcylation of lysosomal Cathepsin B to promote cancer metastasis and chemoresistance. Cancer Cell 2022; 40(10): 1207–1222.e10

[34] Chen DP, Ning WR, Li XF, Wei Y, Lao XM, Wang JC, Wu Y, Zheng L. Peritumoral monocytes induce cancer cell autophagy to facilitate the progression of human hepatocellular carcinoma. Autophagy 2018; 14(8): 1335–1346

[35] Xu ZQ, Zhao L, Zhu LY, He M, Zheng L, Wu Y. MicroRNA-17, 20a regulates the proangiogenic function of tumor-associated macrophages via targeting hypoxia-inducible factor 2α. PLoS One 2013; 8(10): e77890

[36] Hongu T, Pein M, Insua-Rodríguez J, Gutjahr E, Mattavelli G, Meier J, Decker K, Descot A, Bozza M, Harbottle R, Trumpp A, Sinn HP, Riedel A, Oskarsson T. Perivascular tenascin C triggers sequential activation of macrophages and endothelial cells to generate a pro-metastatic vascular niche in the lungs. Nat Can 2022; 3(4): 486–504

[37] Mirzapour MH, Heidari-Foroozan M, Razi S, Rezaei N. The pro-tumorigenic responses in metastatic niches: an immunological perspective. Clin Transl Oncol 2023; 25(2): 333–344

[38] DeNardo DG, Ruffell B. Macrophages as regulators of tumour immunity and immunotherapy. Nat Rev Immunol 2019; 19(6): 369–382

[39] Morrissey SM, Zhang F, Ding C, Montoya-Durango DE, Hu X, Yang C, Wang Z, Yuan F, Fox M, Zhang H, Guo H, Tieri D, Kong M, Watson CT, Mitchell RA, Zhang X, McMasters KM, Huang J, Yan J. Tumor-derived exosomes drive immunosuppressive macrophages in a pre-metastatic niche through glycolytic dominant metabolic reprogramming. Cell Metab 2021; 33(10): 2040–2058.e10

[40] Lasser SA, Ozbay Kurt FG, Arkhypov I, Utikal J, Umansky V. Myeloid-derived suppressor cells in cancer and cancer therapy. Nat Rev Clin Oncol 2024; 21(2): 147–164

[41] Liu ZD, Zhang ZM. Mapping cell types across human tissues. Science 2022; 376(6594): 695–696

[42] Xue RD, Zhang Q, Cao Q, Kong R, Xiang X, Liu H, Feng M, Wang F, Cheng J, Li Z, Zhan Q, Deng M, Zhu J, Zhang Z, Zhang N. Liver tumour immune microenvironment subtypes and neutrophil heterogeneity. Nature 2022; 612(7938): 141–147

[43] Kuang DM, Zhao Q, Xu J, Yun JP, Wu C, Zheng L. Tumor-educated tolerogenic dendritic cells induce CD3ε down-regulation and apoptosis of T cells through oxygen-dependent pathways. J Immunol 2008; 181(5): 3089–3098

[44] Geiger R, Rieckmann JC, Wolf T, Basso C, Feng Y, Fuhrer T, Kogadeeva M, Picotti P, Meissner F, Mann M, Zamboni N, Sallusto F, Lanzavecchia A. L-arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell 2016; 167(3): 829–842.e13

[45] Martinez FO, Gordon S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep 2014; 6: 6

[46] Raber P, Ochoa AC, Rodríguez PC. Metabolism of L-arginine by myeloid-derived suppressor cells in cancer: mechanisms of T cell suppression and therapeutic perspectives. Immunol Invest 2012; 41(6-7): 614–634

[47] Rodriguez PC, Quiceno DG, Zabaleta J, Ortiz B, Zea AH, Piazuelo MB, Delgado A, Correa P, Brayer J, Sotomayor EM, Antonia S, Ochoa JB, Ochoa AC. Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses. Cancer Res 2004; 64(16): 5839–5849

[48] Munn DH, Shafizadeh E, Attwood JT, Bondarev I, Pashine A, Mellor AL. Inhibition of T cell proliferation by macrophage tryptophan catabolism. J Exp Med 1999; 189(9): 1363–1372

[49] Frumento G, Rotondo R, Tonetti M, Damonte G, Benatti U, Ferrara GB. Tryptophan-derived catabolites are responsible for inhibition of T and natural killer cell proliferation induced by indoleamine 2, 3-dioxygenase. J Exp Med 2002; 196(4): 459–468

[50] Munn DH, Sharma MD, Baban B, Harding HP, Zhang Y, Ron D, Mellor AL. GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2, 3-dioxygenase. Immunity 2005; 22(5): 633–642

[51] Chiesa MD, Carlomagno S, Frumento G, Balsamo M, Cantoni C, Conte R, Moretta L, Moretta A, Vitale M. The tryptophan catabolite L-kynurenine inhibits the surface expression of NKp46-and NKG2D-activating receptors and regulates NK-cell function. Blood 2006; 108(13): 4118–4125

[52] Mezrich JD, Fechner JH, Zhang X, Johnson BP, Burlingham WJ, Bradfield CA. An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J Immunol 2010; 185(6): 3190–3198

[53] Movahedi K, Laoui D, Gysemans C, Baeten M, Stangé G, Van den Bossche J, Mack M, Pipeleers D, In’t Veld P, De Baetselier P, Van Ginderachter JA. Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C (high) monocytes. Cancer Res 2010; 70(14): 5728–5739

[54] Marigo I, Zilio S, Desantis G, Mlecnik B, Agnellini AHR, Ugel S, Sasso MS, Qualls JE, Kratochvill F, Zanovello P, Molon B, Ries CH, Runza V, Hoves S, Bilocq AM, Bindea G, Mazza EMC, Bicciato S, Galon J, Murray PJ, Bronte V. T cell cancer therapy requires CD40–CD40L activation of tumor necrosis factor and inducible nitric-oxide-synthase-producing dendritic cells. Cancer Cell 2016; 30(3): 377–390

[55] Kusmartsev S, Gabrilovich DI. STAT1 signaling regulates tumor-associated macrophage-mediated T cell deletion. J Immunol 2005; 174(8): 4880–4891

[56] Nagaraj S, Gupta K, Pisarev V, Kinarsky L, Sherman S, Kang L, Herber DL, Schneck J, Gabrilovich DI. Altered recognition of antigen is a mechanism of CD8⁺ T cell tolerance in cancer. Nat Med 2007; 13(7): 828–835

[57] Schmielau J, Finn OJ. Activated granulocytes and granulocyte-derived hydrogen peroxide are the underlying mechanism of suppression of t-cell function in advanced cancer patients. Cancer Res 2001; 61(12): 4756–4760

[58] Corzo CA, Cotter MJ, Cheng P, Cheng F, Kusmartsev S, Sotomayor E, Padhya T, McCaffrey TV, McCaffrey JC, Gabrilovich DI. Mechanism regulating reactive oxygen species in tumor-induced myeloid-derived suppressor cells. J Immunol 2009; 182(9): 5693–5701

[59] Hamilton MJ, Bosiljcic M, LePard NE, Halvorsen EC, Ho VW, Banáth JP, Krystal G, Bennewith KL. Macrophages are more potent immune suppressors ex vivo than immature myeloid-derived suppressor cells induced by metastatic murine mammary carcinomas. J Immunol 2014; 192(1): 512–522

[60] OuYang LY, Wu XJ, Ye SB, Zhang R, Li ZL, Liao W, Pan ZZ, Zheng LM, Zhang XS, Wang Z, Li Q, Ma G, Li J. Tumor-induced myeloid-derived suppressor cells promote tumor progression through oxidative metabolism in human colorectal cancer. J Transl Med 2015; 13(1): 1–12

[61] Antonioli L, Pacher P, Vizi ES, Haskó G. CD39 and CD73 in immunity and inflammation. Trends Mol Med 2013; 19(6): 355–367

[62] Takenaka MC, Gabriely G, Rothhammer V, Mascanfroni ID, Wheeler MA, Chao CC, Gutiérrez-Vázquez C, Kenison J, Tjon EC, Barroso A, Vandeventer T, de Lima KA, Rothweiler S, Mayo L, Ghannam S, Zandee S, Healy L, Sherr D, Farez MF, Prat A, Antel J, Reardon DA, Zhang H, Robson SC, Getz G, Weiner HL, Quintana FJ. Control of tumor-associated macrophages and T cells in glioblastoma via AHR and CD39. Nat Neurosci 2019; 22(5): 729–740

[63] Ruffell B, Chang-Strachan D, Chan V, Rosenbusch A, Ho CMT, Pryer N, Daniel D, Hwang ES, Rugo HS, Coussens LM. Macrophage IL-10 blocks CD8⁺ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells. Cancer Cell 2014; 26(5): 623–637

[64] Moore KW, de Waal Malefyt R, Coffman RL, O’Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 2001; 19(1): 683–765

[65] Hart KM, Byrne KT, Molloy MJ, Usherwood EM, Berwin B. IL-10 immunomodulation of myeloid cells regulates a murine model of ovarian cancer. Front Immunol 2011; 2: 29

[66] Ip WE, Hoshi N, Shouval DS, Snapper S, Medzhitov R. Anti-inflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages. Science 2017; 356(6337): 513–519

[67] Krawczyk CM, Holowka T, Sun J, Blagih J, Amiel E, DeBerardinis RJ, Cross JR, Jung E, Thompson CB, Jones RG, Pearce EJ. Toll-like receptor–induced changes in glycolytic metabolism regulate dendritic cell activation. Blood 2010; 115(23): 4742–4749

[68] Smith LK, Boukhaled GM, Condotta SA, Mazouz S, Guthmiller JJ, Vijay R, Butler NS, Bruneau J, Shoukry NH, Krawczyk CM, Richer MJ. Interleukin-10 directly inhibits CD8⁺ T cell function by enhancing N-glycan branching to decrease antigen sensitivity. Immunity 2018; 48(2): 299–312.e5

[69] Li H, Han Y, Guo Q, Zhang M, Cao X. Cancer-expanded myeloid-derived suppressor cells induce anergy of NK cells through membrane-bound TGF-β1. J Immunol 2009; 182(1): 240–249

[70] Peng L, Zhang J, Teng Y, Zhao Y, Wang T, Mao F, Lv Y, Cheng P, Li W, Chen N, Duan M, Chen W, Guo G, Zou Q, Zhuang Y. Tumor-associated monocytes/macrophages impair NK-cell function via TGFβ1 in human gastric cancer. Cancer Immunol Res 2017; 5(3): 248–256

[71] Batlle E, Massague J. Transforming growth factor-beta signaling in immunity and cancer. Immunity 2019; 50(4): 924–940

[72] Ma X, Gao Y, Chen Y, Liu J, Yang C, Bao C, Wang Y, Feng Y, Song X, Qiao S. M2-type macrophages induce tregs generation by activating the TGF-β/Smad signalling pathway to promote colorectal cancer development. OncoTargets Ther 2021; 14: 5391–5402

[73] Kos K, Salvagno C, Wellenstein MD, Aslam MA, Meijer DA, Hau CS, Vrijland K, Kaldenbach D, Raeven EAM, Schmittnaegel M, Ries CH, de Visser KE. Tumor-associated macrophages promote intratumoral conversion of conventional CD4⁺ T cells into regulatory T cells via PD-1 signalling. OncoImmunology 2022; 11(1): 2063225

[74] Wu Y, Kuang DM, Pan WD, Wan YL, Lao XM, Wang D, Li XF, Zheng L. Monocyte/macrophage-elicited natural killer cell dysfunction in hepatocellular carcinoma is mediated by CD48/2B4 interactions. Hepatology 2013; 57(3): 1107–1116

[75] Park MD, Reyes-Torres I, LeBerichel J, Hamon P, LaMarche NM, Hegde S, Belabed M, Troncoso L, Grout JA, Magen A, Humblin E, Nair A, Molgora M, Hou J, Newman JH, Farkas AM, Leader AM, Dawson T, D’Souza D, Hamel S, Sanchez-Paulete AR, Maier B, Bhardwaj N, Martin JC, Kamphorst AO, Kenigsberg E, Casanova-Acebes M, Horowitz A, Brown BD, De Andrade LF, Colonna M, Marron TU, Merad M. TREM2 macrophages drive NK cell paucity and dysfunction in lung cancer. Nat Immunol 2023; 24(5): 792–801

[76] Kuang DM, Xiao X, Zhao Q, Chen MM, Li XF, Liu RX, Wei Y, Ouyang FZ, Chen DP, Wu Y, Lao XM, Deng H, Zheng L. B7–H1-expressing antigen-presenting cells mediate polarization of protumorigenic Th22 subsets. J Clin Invest 2014; 124(10): 4657–4667

[77] Kersten K, Hu KH, Combes AJ, Samad B, Harwin T, Ray A, Rao AA, Cai E, Marchuk K, Artichoker J, Courau T, Shi Q, Belk J, Satpathy AT, Krummel MF. Spatiotemporal co-dependency between macrophages and exhausted CD8⁺ T cells in cancer. Cancer Cell 2022; 40(6): 624–638.e9

[78] Chow A, Schad S, Green MD, Hellmann MD, Allaj V, Ceglia N, Zago G, Shah NS, Sharma SK, Mattar M, Chan J, Rizvi H, Zhong H, Liu C, Bykov Y, Zamarin D, Shi H, Budhu S, Wohlhieter C, Uddin F, Gupta A, Khodos I, Waninger JJ, Qin A, Markowitz GJ, Mittal V, Balachandran V, Durham JN, Le DT, Zou W, Shah SP, McPherson A, Panageas K, Lewis JS, Perry JSA, de Stanchina E, Sen T, Poirier JT, Wolchok JD, Rudin CM, Merghoub T. Tim-4⁺ cavity-resident macrophages impair anti-tumor CD8⁺ T cell immunity. Cancer Cell 2021; 39(7): 973–988.e9

[79] Laumont CM, Banville AC, Gilardi M, Hollern DP, Nelson BH. Tumour-infiltrating B cells: immunological mechanisms, clinical impact and therapeutic opportunities. Nat Rev Cancer 2022; 22(7): 414–430

[80] Wu RQ, Lao XM, Chen DP, Qin H, Mu M, Cao WJ, Deng J, Wan CC, Zhan WY, Wang JC, Xu L, Chen MS, Gao Q, Zheng L, Wei Y, Kuang DM. Immune checkpoint therapy-elicited sialylation of IgG antibodies impairs antitumorigenic type I interferon responses in hepatocellular carcinoma. Immunity 2023; 56(1): 180–192.e11

[81] Chen Z, Zhang G, Ren X, Yao Z, Zhou Q, Ren X, Chen S, Xu L, Sun K, Zeng Q, Kuang M, Kuang DM, Peng S. Cross-talk between myeloid and B cells shapes the distinct microenvironments of primary and secondary liver cancer. Cancer Res 2023; 83(21): 3544–3561

[82] Shaul ME, Zlotnik A, Tidhar E, Schwartz A, Arpinati L, Kaisar-Iluz N, Mahroum S, Mishalian I, Fridlender ZG. Tumor-associated neutrophils drive B-cell recruitment and their differentiation to plasma cells. Cancer Immunol Res 2021; 9(7): 811–824

[83] Wang Y, Schafer CC, Hough KP, Tousif S, Duncan SR, Kearney JF, Ponnazhagan S, Hsu HC, Deshane JS. Myeloid-derived suppressor cells impair B cell responses in lung cancer through IL-7 and STAT5. J Immunol 2018; 201(1): 278–295

[84] Peng ZP, Jiang ZZ, Guo HF, Zhou MM, Huang YF, Ning WR, Huang JH, Zheng L, Wu Y. Glycolytic activation of monocytes regulates the accumulation and function of neutrophils in human hepatocellular carcinoma. J Hepatol 2020; 73(4): 906–917

[85] Matusiak M, Hickey JW, van IJzendoorn DGP, Lu G, Kidziński L, Zhu S, Colburg DRC, Luca B, Phillips DJ, Brubaker SW, Charville GW, Shen J, Loh KM, Okwan-Duodu DK, Nolan GP, Newman AM, West RB, van de Rijn M. Spatially segregated macrophage populations predict distinct outcomes in colon cancer. Cancer Discov 2024; 14(8): 1418–1439

[86] Sinha P, Clements VK, Bunt SK, Albelda SM, Ostrand-Rosenberg S. Cross-talk between myeloid-derived suppressor cells and macrophages subverts tumor immunity toward a type 2 response. J Immunol 2007; 179(2): 977–983

[87] Bunt SK, Clements VK, Hanson EM, Sinha P, Ostrand-Rosenberg S. Inflammation enhances myeloid-derived suppressor cell cross-talk by signaling through Toll-like receptor 4. J Leukoc Biol 2009; 85(6): 996–1004

[88] Thibodeau J, Bourgeois-Daigneault MC, Huppé G, Tremblay J, Aumont A, Houde M, Bartee E, Brunet A, Gauvreau ME, de Gassart A, Gatti E, Baril M, Cloutier M, Bontron S, Früh K, Lamarre D, Steimle V. Interleukin-10-induced MARCH1 mediates intracellular sequestration of MHC class II in monocytes. Eur J Immunol 2008; 38(5): 1225–1230

[89] Kwak T, Wang F, Deng H, Condamine T, Kumar V, Perego M, Kossenkov A, Montaner LJ, Xu X, Xu W, Zheng C, Schuchter LM, Amaravadi RK, Mitchell TC, Karakousis GC, Mulligan C, Nam B, Masters G, Hockstein N, Bennett J, Nefedova Y, Gabrilovich DI. Distinct populations of immune-suppressive macrophages differentiate from monocytic myeloid-derived suppressor cells in cancer. Cell Rep 2020; 33(13): 108571

[90] Corzo CA, Condamine T, Lu L, Cotter MJ, Youn JI, Cheng P, Cho HI, Celis E, Quiceno DG, Padhya T, McCaffrey TV, McCaffrey JC, Gabrilovich DI. HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J Exp Med 2010; 207(11): 2439–2453

[91] Zhang Y, Li JQ, Jiang ZZ, Li L, Wu Y, Zheng L. CD169 identifies an anti-tumour macrophage subpopulation in human hepatocellular carcinoma. J Pathol 2016; 239(2): 231–241

[92] Nalio Ramos R, Missolo-Koussou Y, Gerber-Ferder Y, Bromley CP, Bugatti M, Núñez NG, Tosello Boari J, Richer W, Menger L, Denizeau J, Sedlik C, Caudana P, Kotsias F, Niborski LL, Viel S, Bohec M, Lameiras S, Baulande S, Lesage L, Nicolas A, Meseure D, Vincent-Salomon A, Reyal F, Dutertre CA, Ginhoux F, Vimeux L, Donnadieu E, Buttard B, Galon J, Zelenay S, Vermi W, Guermonprez P, Piaggio E, Helft J. Tissue-resident FOLR2⁺ macrophages associate with CD8⁺ T cell infiltration in human breast cancer. Cell 2022; 185(7): 1189–1207.e25

[93] Liu CQ, Xu J, Zhou ZG, Jin LL, Yu XJ, Xiao G, Lin J, Zhuang SM, Zhang YJ, Zheng L. Expression patterns of programmed death ligand 1 correlate with different microenvironments and patient prognosis in hepatocellular carcinoma. Br J Cancer 2018; 119(1): 80–88

[94] Wang L, Guo W, Guo Z, Yu J, Tan J, Simons DL, Hu K, Liu X, Zhou Q, Zheng Y, Colt EA, Yim J, Waisman J, Lee PP. PD-L1-expressing tumor-associated macrophages are immunostimulatory and associate with good clinical outcome in human breast cancer. Cell Rep Med 2024; 5(2): 101420

[95] O’Neill LAJ, Kishton RJ, Rathmell J. A guide to immunometabolism for immunologists. Nat Rev Immunol 2016; 16(9): 553–565

[96] Liu J, Cao X. Glucose metabolism of TAMs in tumor chemoresistance and metastasis. Trends Cell Biol 2023; 33(11): 967–978

[97] Reinfeld BI, Madden MZ, Wolf MM, Chytil A, Bader JE, Patterson AR, Sugiura A, Cohen AS, Ali A, Do BT, Muir A, Lewis CA, Hongo RA, Young KL, Brown RE, Todd VM, Huffstater T, Abraham A, O’Neil RT, Wilson MH, Xin F, Tantawy MN, Merryman WD, Johnson RW, Williams CS, Mason EF, Mason FM, Beckermann KE, Vander Heiden MG, Manning HC, Rathmell JC, Rathmell WK. Cell-programmed nutrient partitioning in the tumour microenvironment. Nature 2021; 593(7858): 282–288

[98] Penny HL, Sieow JL, Gun SY, Lau MC, Lee B, Tan J, Phua C, Toh F, Nga Y, Yeap WH, Janela B, Kumar D, Chen H, Yeong J, Kenkel JA, Pang A, Lim D, Toh HC, Hon TLK, Johnson CI, Khameneh HJ, Mortellaro A, Engleman EG, Rotzschke O, Ginhoux F, Abastado JP, Chen J, Wong SC. Targeting glycolysis in macrophages confers protection against pancreatic ductal adenocarcinoma. Int J Mol Sci 2021; 22(12): 1–1

[99] Fu C, Fu Z, Jiang C, Xia C, Zhang Y, Gu X, Zheng K, Zhou D, Tang S, Lyu S, Ma S. CD205⁺ polymorphonuclear myeloid-derived suppressor cells suppress antitumor immunity by overexpressing GLUT3. Cancer Sci 2021; 112(3): 1011–1025

[100] De Leo A, Ugolini A, Yu X, Scirocchi F, Scocozza D, Peixoto B, Pace A, D’Angelo L, Liu JKC, Etame AB, Rughetti A, Nuti M, Santoro A, Vogelbaum MA, Conejo-Garcia JR, Rodriguez PC, Veglia F. Glucose-driven histone lactylation promotes the immunosuppressive activity of monocyte-derived macrophages in glioblastoma. Immunity 2024; 57(5): 1105–1123.e8

[101] Chen DP, Ning WR, Jiang ZZ, Peng ZP, Zhu LY, Zhuang SM, Kuang DM, Zheng L, Wu Y. Glycolytic activation of peritumoral monocytes fosters immune privilege via the PFKFB3-PD-L1 axis in human hepatocellular carcinoma. J Hepatol 2019; 71(2): 333–343

[102] Larionova I, Patysheva M, Iamshchikov P, Kazakova E, Kazakova A, Rakina M, Grigoryeva E, Tarasova A, Afanasiev S, Bezgodova N, Kiselev A, Dobrodeev A, Kostromitskiy D, Cherdyntseva N, Kzhyshkowska J. PFKFB3 overexpression in monocytes of patients with colon but not rectal cancer programs pro-tumor macrophages and is indicative for higher risk of tumor relapse. Front Immunol 2023; 13: 1080501

[103] Chen M, Liu H, Li Z, Ming AL, Chen H. Mechanism of PKM2 affecting cancer immunity and metabolism in tumor microenvironment. J Cancer 2021; 12(12): 3566–3574

[104] Wenes M, Shang M, Di Matteo M, Goveia J, Martín-Pérez R, Serneels J, Prenen H, Ghesquière B, Carmeliet P, Mazzone M. Macrophage metabolism controls tumor blood vessel morphogenesis and metastasis. Cell Metab 2016; 24(5): 701–715

[105] Chen D, Xie J, Fiskesund R, Dong W, Liang X, Lv J, Jin X, Liu J, Mo S, Zhang T, Cheng F, Zhou Y, Zhang H, Tang K, Ma J, Liu Y, Huang B. Chloroquine modulates antitumor immune response by resetting tumor-associated macrophages toward M1 phenotype. Nat Commun 2018; 9(1): 873

[106] Zhang Z, Zheng Y, Chen Y, Yin Y, Chen Y, Chen Q, Hou Y, Shen S, Lv M, Wang T. Gut fungi enhances immunosuppressive function of myeloid-derived suppressor cells by activating PKM2-dependent glycolysis to promote colorectal tumorigenesis. Exp Hematol Oncol 2022; 11(1): 88

[107] Yang X, Lu Y, Hang J, Zhang J, Zhang T, Huo Y, Liu J, Lai S, Luo D, Wang L, Hua R, Lin Y. Lactate-modulated immunosuppression of myeloid-derived suppressor cells contributes to the radioresistance of pancreatic cancer. Cancer Immunol Res 2020; 8(11): 1440–1451

[108] Baumann T, Dunkel A, Schmid C, Schmitt S, Hiltensperger M, Lohr K, Laketa V, Donakonda S, Ahting U, Lorenz-Depiereux B, Heil JE, Schredelseker J, Simeoni L, Fecher C, Körber N, Bauer T, Hüser N, Hartmann D, Laschinger M, Eyerich K, Eyerich S, Anton M, Streeter M, Wang T, Schraven B, Spiegel D, Assaad F, Misgeld T, Zischka H, Murray PJ, Heine A, Heikenwälder M, Korn T, Dawid C, Hofmann T, Knolle PA, Höchst B. Regulatory myeloid cells paralyze T cells through cell-cell transfer of the metabolite methylglyoxal. Nat Immunol 2020; 21(5): 555–566

[109] El-Kenawi A, Gatenbee C, Robertson-Tessi M, Bravo R, Dhillon J, Balagurunathan Y, Berglund A, Vishvakarma N, Ibrahim-Hashim A, Choi J, Luddy K, Gatenby R, Pilon-Thomas S, Anderson A, Ruffell B, Gillies R. Acidity promotes tumour progression by altering macrophage phenotype in prostate cancer. Br J Cancer 2019; 121(7): 556–566

[110] Frank AC, Raue R, Fuhrmann DC, Sirait-Fischer E, Reuse C, Weigert A, Lütjohann D, Hiller K, Syed SN, Brüne B. Lactate dehydrogenase B regulates macrophage metabolism in the tumor microenvironment. Theranostics 2021; 11(15): 7570–7588

[111] Apostolova P, Pearce EL. Lactic acid and lactate: revisiting the physiological roles in the tumor microenvironment. Trends Immunol 2022; 43(12): 969–977

[112] Barbato A, Giallongo C, Giallongo S, Romano A, Scandura G, Concetta S, Zuppelli T, Lolicato M, Lazzarino G, Parrinello N, Del Fabro V, Fontana P, Aguennoz M, Li Volti G, Palumbo GA, Di Raimondo F, Tibullo D. Lactate trafficking inhibition restores sensitivity to proteasome inhibitors and orchestrates immuno-microenvironment in multiple myeloma. Cell Prolif 2023; 56(4): e13388

[113] Zhao JL, Ye YC, Gao CC, Wang L, Ren KX, Jiang R, Hu SJ, Liang SQ, Bai J, Liang JL, Ma PF, Hu YY, Li BC, Nie YZ, Chen Y, Li XF, Zhang W, Han H, Qin HY. Notch-mediated lactate metabolism regulates MDSC development through the Hes1/MCT2/c-Jun axis. Cell Rep 2022; 38(10): 110451

[114] Zhang D, Tang Z, Huang H, Zhou G, Cui C, Weng Y, Liu W, Kim S, Lee S, Perez-Neut M, Ding J, Czyz D, Hu R, Ye Z, He M, Zheng YG, Shuman HA, Dai L, Ren B, Roeder RG, Becker L, Zhao Y. Metabolic regulation of gene expression by histone lactylation. Nature 2019; 574(7779): 575–580

[115] Li XM, Yang Y, Jiang FQ, Hu G, Wan S, Yan WY, He XS, Xiao F, Yang XM, Guo X, Lu JH, Yang XQ, Chen JJ, Ye WL, Liu Y, He K, Duan HX, Zhou YJ, Gan WJ, Liu F, Wu H. Histone lactylation inhibits RARγ expression in macrophages to promote colorectal tumorigenesis through activation of TRAF6-IL-6-STAT3 signaling. Cell Rep 2024; 43(2): 113688–1

[116] Zhu CX, Yan K, Chen L, Huang RR, Bian ZH, Wei HR, Gu XM, Zhao YY, Liu MC, Suo CX, Li ZK, Yang ZY, Lu MQ, Hua XF, Li L, Zhao ZB, Sun LC, Zhang HF, Gao P, Lian ZX. Targeting OXCT1-mediated ketone metabolism reprograms macrophages to promote antitumor immunity via CD8⁺ T cells in hepatocellular carcinoma. J Hepatol. 2024; 81(4): 690–703

[117] Alexander RK, Liou YH, Knudsen NH, Starost KA, Xu C, Hyde AL, Liu S, Jacobi D, Liao NS, Lee CH. Bmal1 integrates mitochondrial metabolism and macrophage activation. eLife 2020; 9: e54090

[118] Chen YJ, Li GN, Li XJ, Wei LX, Fu MJ, Cheng ZL, Yang Z, Zhu GQ, Wang XD, Zhang C, Zhang JY, Sun YP, Saiyin H, Zhang J, Liu WR, Zhu WW, Guan KL, Xiong Y, Yang Y, Ye D, Chen LL. Targeting IRG1 reverses the immunosuppressive function of tumor-associated macrophages and enhances cancer immunotherapy. Sci Adv 2023; 9(17): eadg0654

[119] Wang X, Su S, Zhu Y, Cheng X, Cheng C, Chen L, Lei A, Zhang L, Xu Y, Ye D, Zhang Y, Li W, Zhang J. Metabolic Reprogramming via ACOD1 depletion enhances function of human induced pluripotent stem cell-derived CAR-macrophages in solid tumors. Nat Commun 2023; 14(1): 5778

[120] Udumula MP, Sakr S, Dar S, Alvero AB, Ali-Fehmi R, Abdulfatah E, Li J, Jiang J, Tang A, Buekers T, Morris R, Munkarah A, Giri S, Rattan R. Ovarian cancer modulates the immunosuppressive function of CD11b⁺Gr1⁺ myeloid cells via glutamine metabolism. Mol Metab 2021; 53: 101272

[121] Daneshmandi S, Choi JE, Yan Q, MacDonald CR, Pandey M, Goruganthu M, Roberts N, Singh PK, Higashi RM, Lane AN, Fan TWM, Wang J, McCarthy PL, Repasky EA, Mohammadpour H. Myeloid-derived suppressor cell mitochondrial fitness governs chemotherapeutic efficacy in hematologic malignancies. Nat Commun 2024; 15(1): 2803

[122] Zhao H, Teng D, Yang L, Xu X, Chen J, Jiang T, Feng AY, Zhang Y, Frederick DT, Gu L, Cai L, Asara JM, Pasca di Magliano M, Boland GM, Flaherty KT, Swanson KD, Liu D, Rabinowitz JD, Zheng B. Myeloid-derived itaconate suppresses cytotoxic CD8⁺ T cells and promotes tumour growth. Nat Metab 2022; 4(12): 1660–1673

[123] Rodrigues Mantuano N, Stanczak MA, Oliveira IA, Kirchhammer N, Filardy AA, Monaco G, Santos RC, Fonseca AC, Fontes M, Bastos CS Jr, Dias WB, Zippelius A, Todeschini AR, Läubli H. Hyperglycemia enhances cancer immune evasion by inducing alternative macrophage polarization through increased O-GlcNAcylation. Cancer Immunol Res 2020; 8(10): 1262–1272

[124] Hinshaw DC, Hanna A, Lama-Sherpa T, Metge B, Kammerud SC, Benavides GA, Kumar A, Alsheikh HA, Mota M, Chen D, Ballinger SW, Rathmell JC, Ponnazhagan S, Darley-Usmar V, Samant RS, Shevde LA. Hedgehog signaling regulates metabolism and polarization of mammary tumor-associated macrophages. Cancer Res 2021; 81(21): 5425–5437

[125] Yan J, Horng T. Lipid metabolism in regulation of macrophage functions. Trends Cell Biol 2020; 30(12): 979–989

[126] Rabold K, Aschenbrenner A, Thiele C, Boahen CK, Schiltmans A, Smit JWA, Schultze JL, Netea MG, Adema GJ, Netea-Maier RT. Enhanced lipid biosynthesis in human tumor-induced macrophages contributes to their protumoral characteristics. J Immunother Cancer 2020; 8(2): e000638

[127] Liu C, Chikina M, Deshpande R, Menk AV, Wang T, Tabib T, Brunazzi EA, Vignali KM, Sun M, Stolz DB, Lafyatis RA, Chen W, Delgoffe GM, Workman CJ, Wendell SG, Vignali DAA. Treg cells promote the SREBP1-dependent metabolic fitness of tumor-promoting macrophages via repression of CD8⁺ T cell-derived interferon-γ. Immunity 2019; 51(2): 381–397.e6

[128] Liu M, O’Connor RS, Trefely S, Graham K, Snyder NW, Beatty GL. Metabolic rewiring of macrophages by CpG potentiates clearance of cancer cells and overcomes tumor-expressed CD47-mediated ‘don’t-eat-me’ signal. Nat Immunol 2019; 20(3): 265–275

[129] Song C, Ji Y, Wang W, Tao N. Ginger polysaccharide promotes myeloid-derived suppressor cell apoptosis by regulating lipid metabolism. Phytother Res 2023; 37(7): 2894–2901

[130] Yan G, Zhao H, Zhang Q, Zhou Y, Wu L, Lei J, Wang X, Zhang J, Zhang X, Zheng L, Du G, Xiao W, Tang B, Miao H, Li Y. A RIPK3–PGE2 circuit mediates myeloid-derived suppressor cell-potentiated colorectal carcinogenesis. Cancer Res 2018; 78(19): 5586–5599

[131] Dai E, Han L, Liu J, Xie Y, Kroemer G, Klionsky DJ, Zeh HJ, Kang R, Wang J, Tang D. Autophagy-dependent ferroptosis drives tumor-associated macrophage polarization via release and uptake of oncogenic KRAS protein. Autophagy 2020; 16(11): 2069–2083

[132] Liu S, Zhang H, Li Y, Zhang Y, Bian Y, Zeng Y, Yao X, Wan J, Chen X, Li J, Wang Z, Qin Z. S100A4 enhances protumor macrophage polarization by control of PPAR-γ-dependent induction of fatty acid oxidation. J Immunother Cancer 2021; 9(6): e002548

[133] Liu PS, Chen YT, Li X, Hsueh PC, Tzeng SF, Chen H, Shi PZ, Xie X, Parik S, Planque M, Fendt SM, Ho PC. CD40 signal rewires fatty acid and glutamine metabolism for stimulating macrophage anti-tumorigenic functions. Nat Immunol 2023; 24(3): 452–462

[134] Hossain F, Al-Khami AA, Wyczechowska D, Hernandez C, Zheng L, Reiss K, Valle LD, Trillo-Tinoco J, Maj T, Zou W, Rodriguez PC, Ochoa AC. Inhibition of fatty acid oxidation modulates immunosuppressive functions of myeloid-derived suppressor cells and enhances cancer therapies. Cancer Immunol Res 2015; 3(11): 1236–1247

[135] Xin G, Chen Y, Topchyan P, Kasmani MY, Burns R, Volberding PJ, Wu X, Cohn A, Chen Y, Lin CW, Ho PC, Silverstein R, Dwinell MB, Cui W. Targeting PIM1-mediated metabolism in myeloid suppressor cells to treat cancer. Cancer Immunol Res 2021; 9(4): 454–469

[136] Mohammadpour H, MacDonald CR, McCarthy PL, Abrams SI, Repasky EA. β2-adrenergic receptor signaling regulates metabolic pathways critical to myeloid-derived suppressor cell function within the TME. Cell Rep 2021; 37(4): 109883

[137] Wang Y, Chen W, Qiao S, Zou H, Yu X, Yang Y, Li Z, Wang J, Chen M, Xu J, Zheng L. Lipid droplet accumulation mediates macrophage survival and Treg recruitment via the CCL20/CCR6 axis in human hepatocellular carcinoma. Cell Mol Immunol 2024; 21(10): 1120–1130

[138] Yang P, Qin H, Li Y, Xiao A, Zheng E, Zeng H, Su C, Luo X, Lu Q, Liao M, Zhao L, Wei L, Varghese Z, Moorhead JF, Chen Y, Ruan XZ. CD36-mediated metabolic crosstalk between tumor cells and macrophages affects liver metastasis. Nat Commun 2022; 13(1): 5782

[139] Zhou L, Wang M, Guo H, Hou J, Zhang Y, Li M, Wu X, Chen X, Wang L. Integrated analysis highlights the immunosuppressive role of TREM2⁺ macrophages in hepatocellular carcinoma. Front Immunol. 2022; 13: 848367

[140] Huggins DN, LaRue RS, Wang Y, Knutson TP, Xu Y, Williams JW, Schwertfeger KL. Characterizing macrophage diversity in metastasis-bearing lungs reveals a lipid-associated macrophage subset. Cancer Res 2021; 81(20): 5284–5295

[141] Di Conza G, Tsai CH, Gallart-Ayala H, Yu YR, Franco F, Zaffalon L, Xie X, Li X, Xiao Z, Raines LN, Falquet M, Jalil A, Locasale JW, Percipalle P, Masson D, Huang SCC, Martinon F, Ivanisevic J, Ho PC. Tumor-induced reshuffling of lipid composition on the endoplasmic reticulum membrane sustains macrophage survival and pro-tumorigenic activity. Nat Immunol 2021; 22(11): 1403–1415

[142] Masetti M, Carriero R, Portale F, Marelli G, Morina N, Pandini M, Iovino M, Partini B, Erreni M, Ponzetta A, Magrini E, Colombo P, Elefante G, Colombo FS, den Haan JMM, Peano C, Cibella J, Termanini A, Kunderfranco P, Brummelman J, Chung MWH, Lazzeri M, Hurle R, Casale P, Lugli E, DePinho RA, Mukhopadhyay S, Gordon S, Di Mitri D. Lipid-loaded tumor-associated macrophages sustain tumor growth and invasiveness in prostate cancer. J Exp Med 2022; 219(2): e20210564

[143] Veglia F, Tyurin VA, Blasi M, De Leo A, Kossenkov AV, Donthireddy L, To TKJ, Schug Z, Basu S, Wang F, Ricciotti E, DiRusso C, Murphy ME, Vonderheide RH, Lieberman PM, Mulligan C, Nam B, Hockstein N, Masters G, Guarino M, Lin C, Nefedova Y, Black P, Kagan VE, Gabrilovich DI. Fatty acid transport protein 2 reprograms neutrophils in cancer. Nature 2019; 569(7754): 73–78

[144] Ugolini A, Tyurin VA, Tyurina YY, Tcyganov EN, Donthireddy L, Kagan VE, Gabrilovich DI, Veglia F. Polymorphonuclear myeloid-derived suppressor cells limit antigen cross-presentation by dendritic cells in cancer. JCI Insight. 2020; 5(15): e138581

[145] Kim R, Hashimoto A, Markosyan N, Tyurin VA, Tyurina YY, Kar G, Fu S, Sehgal M, Garcia-Gerique L, Kossenkov A, Gebregziabher BA, Tobias JW, Hicks K, Halpin RA, Cvetesic N, Deng H, Donthireddy L, Greenberg A, Nam B, Vonderheide RH, Nefedova Y, Kagan VE, Gabrilovich DI. Ferroptosis of tumour neutrophils causes immune suppression in cancer. Nature 2022; 612(7939): 338–346

[146] Gao C, Huang Q, Liu C, Kwong CHT, Yue L, Wan JB, Lee SMY, Wang R. Treatment of atherosclerosis by macrophage-biomimetic nanoparticles via targeted pharmacotherapy and sequestration of proinflammatory cytokines. Nat Commun 2020; 11(1): 2622

[147] Nakahara R, Aki S, Sugaya M, Hirose H, Kato M, Maeda K, Sakamoto DM, Kojima Y, Nishida M, Ando R, Muramatsu M, Pan M, Tsuchida R, Matsumura Y, Yanai H, Takano H, Yao R, Sando S, Shibuya M, Sakai J, Kodama T, Kidoya H, Shimamura T, Osawa T. Hypoxia activates SREBP2 through Golgi disassembly in bone marrow-derived monocytes for enhanced tumor growth. EMBO J 2023; 42(22): e114032

[148] Lv Q, Zhang Y, Gao W, Wang J, Hu Y, Yang H, Xie Y, Lv Y, Zhang H, Wu D, Hu L, Wang J. CSF1R inhibition reprograms tumor-associated macrophages to potentiate anti-PD-1 therapy efficacy against colorectal cancer. Pharmacol Res 2024; 202: 107126

[149] Dong Y, Zhang J, Wang Y, Zhang Y, Rappaport D, Yang Z, Han M, Liu Y, Fu Z, Zhao X, Tang C, Shi C, Zhang D, Li D, Ni S, Li A, Cui J, Li T, Sun P, Benny O, Zhang C, Zhao K, Chen C, Jiang X. Intracavitary spraying of nanoregulator-encased hydrogel modulates cholesterol metabolism of glioma-supportive macrophage for postoperative glioblastoma immunotherapy. Adv Mater 2024; 36(13): e2311109

[150] Ye Z, Ai X, Yang K, Yang Z, Fei F, Liao X, Qiu Z, Gimple RC, Yuan H, Huang H, Gong Y, Xiao C, Yue J, Huang L, Saulnier O, Wang W, Zhang P, Dai L, Wang X, Wang X, Ahn YH, You C, Xu J, Wan X, Taylor MD, Zhao L, Rich JN, Zhou S. Targeting microglial metabolic rewiring synergizes with immune-checkpoint blockade therapy for glioblastoma. Cancer Discov 2023; 13(4): 974–1001

[151] Liu Y, Wang Z, Jin H, Cui L, Huo B, Xie C, Li J, Ding H, Zhang H, Xiong W, Li M, Zhang H, Guo H, Li C, Wang T, Wang X, He W, Wang Z, Bei JX, Huang P, Liu J, Xia X. Squalene-epoxidase-catalyzed 24(S), 25-epoxycholesterol synthesis promotes trained-immunity-mediated antitumor activity. Cell Rep 2024; 43(4): 114094

[152] Wu L, Liu X, Lei J, Zhang N, Zhao H, Zhang J, Deng H, Li Y. Fibrinogen-like protein 2 promotes tumor immune suppression by regulating cholesterol metabolism in myeloid-derived suppressor cells. J Immunother Cancer 2023; 11(12): e008081

[153] Chen Y, Xu Y, Zhao H, Zhou Y, Zhang J, Lei J, Wu L, Zhou M, Wang J, Yang S, Zhang X, Yan G, Li Y. Myeloid-derived suppressor cells deficient in cholesterol biosynthesis promote tumor immune evasion. Cancer Lett 2023; 564: 216208

[154] Strauss L, Mahmoud MAA, Weaver JD, Tijaro-Ovalle NM, Christofides A, Wang Q, Pal R, Yuan M, Asara J, Patsoukis N, Boussiotis VA. Targeted deletion of PD-1 in myeloid cells induces antitumor immunity. Sci Immunol 2020; 5(43): eaay1863

[155] Xiao J, Wang S, Chen L, Ding X, Dang Y, Han M, Zheng Y, Shen H, Wu S, Wang M, Yang D, Li N, Dong C, Hu M, Su C, Li W, Hui L, Ye Y, Tang H, Wei B, Wang H. 25-hydroxycholesterol regulates lysosome AMP kinase activation and metabolic reprogramming to educate immunosuppressive macrophages. Immunity 2024; 57(5): 1087–1104.e7

[156] Ma L, Wang L, Nelson AT, Han C, He S, Henn MA, Menon K, Chen JJ, Baek AE, Vardanyan A, Shahoei SH, Park S, Shapiro DJ, Nanjappa SG, Nelson ER. 27-Hydroxycholesterol acts on myeloid immune cells to induce T cell dysfunction, promoting breast cancer progression. Cancer Lett 2020; 493: 266–283

[157] Baek AE, Yu YRA, He S, Wardell SE, Chang CY, Kwon S, Pillai RV, McDowell HB, Thompson JW, Dubois LG, Sullivan PM, Kemper JK, Gunn MD, McDonnell DP, Nelson ER. The cholesterol metabolite 27 hydroxycholesterol facilitates breast cancer metastasis through its actions on immune cells. Nat Commun 2017; 8(1): 864

[158] Sag D, Cekic C, Wu R, Linden J, Hedrick CC. The cholesterol transporter ABCG1 links cholesterol homeostasis and tumour immunity. Nat Commun 2015; 6(1): 6354–6367

[159] Goossens P, Rodriguez-Vita J, Etzerodt A, Masse M, Rastoin O, Gouirand V, Ulas T, Papantonopoulou O, Van Eck M, Auphan-Anezin N, Bebien M, Verthuy C, Vu Manh TP, Turner M, Dalod M, Schultze JL, Lawrence T. Membrane cholesterol efflux drives tumor-associated macrophage reprogramming and tumor progression. Cell Metab 2019; 29(6): 1376–1389

[160] El-Kenawi A, Dominguez-Viqueira W, Liu M, Awasthi S, Abraham-Miranda J, Keske A, Steiner KLK, Noel L, Serna AN, Dhillon J, Gillies RJ, Yu X, Koomen JM, Yamoah K, Gatenby RA, Ruffell B. Macrophage-derived cholesterol contributes to therapeutic resistance in prostate cancer. Cancer Res 2021; 81(21): 5477–5490

[161] Li Z, Wang Y, Xing R, Zeng H, Yu XJ, Zhang Y, Xu J, Zheng L. Cholesterol efflux drives the generation of immunosuppressive macrophages to promote the progression of human hepatocellular carcinoma. Cancer Immunol Res 2023; 11(10): 1400–1413

[162] Halaby MJ, McGaha TL. Amino acid transport and metabolism in myeloid function. Front Immunol 2021; 12: 695238

[163] Zhang X, Ji L, Li MO. Control of tumor-associated macrophage responses by nutrient acquisition and metabolism. Immunity 2023; 56(1): 14–31

[164] Cimen Bozkus C, Elzey BD, Crist SA, Ellies LG, Ratliff TL. Expression of cationic amino acid transporter 2 is required for myeloid-derived suppressor cell-mediated control of T cell immunity. J Immunol 2015; 195(11): 5237–5250

[165] Steggerda SM, Bennett MK, Chen J, Emberley E, Huang T, Janes JR, Li W, MacKinnon AL, Makkouk A, Marguier G, Murray PJ, Neou S, Pan A, Parlati F, Rodriguez MLM, Van de Velde LA, Wang T, Works M, Zhang J, Zhang W, Gross MI. Inhibition of arginase by CB-1158 blocks myeloid cell-mediated immune suppression in the tumor microenvironment. J Immunother Cancer 2017; 5(1): 101–1

[166] Sullivan MR, Danai LV, Lewis CA, Chan SH, Gui DY, Kunchok T, Dennstedt EA, Vander Heiden MG, Muir A. Quantification of microenvironmental metabolites in murine cancers reveals determinants of tumor nutrient availability. eLife 2019; 8: e44235

[167] Menjivar RE, Nwosu ZC, Du W, Donahue KL, Hong HS, Espinoza C, Brown K, Velez-Delgado A, Yan W, Lima F, Bischoff A, Kadiyala P, Salas-Escabillas D, Crawford HC, Bednar F, Carpenter E, Zhang Y, Halbrook CJ, Lyssiotis CA, Pasca di Magliano M. Arginase 1 is a key driver of immune suppression in pancreatic cancer. Elife. 2023; 12: e80721

[168] McCubbrey AL, McManus SA, McClendon JD, Thomas SM, Chatwin HB, Reisz JA, D'Alessandro A, Mould KJ, Bratton DL, Henson PM, Janssen WJ. Polyamine import and accumulation causes immunomodulation in macrophages engulfing apoptotic cells. Cell Rep. 2022; 38(2): 110222

[169] Horn LA, Chariou PL, Gameiro SR, Qin H, Iida M, Fousek K, Meyer TJ, Cam M, Flies D, Langermann S, Schlom J, Palena C. Remodeling the tumor microenvironment via blockade of LAIR-1 and TGF-β signaling enables PD-L1-mediated tumor eradication. J Clin Invest 2022; 132(8): e155148

[170] Gao W, Zhang X, Yang W, Dou D, Zhang H, Tang Y, Zhong W, Meng J, Bai Y, Liu Y, Yang L, Chen S, Liu H, Yang C, Sun T. Prim-O-glucosylcimifugin enhances the antitumour effect of PD-1 inhibition by targeting myeloid-derived suppressor cells. J Immunother Cancer 2019; 7(1): 231

[171] Jha AK, Huang SCC, Sergushichev A, Lampropoulou V, Ivanova Y, Loginicheva E, Chmielewski K, Stewart KM, Ashall J, Everts B, Pearce EJ, Driggers EM, Artyomov MN. Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity 2015; 42(3): 419–430

[172] Liu PS, Wang H, Li X, Chao T, Teav T, Christen S, Di Conza G, Cheng WC, Chou CH, Vavakova M, Muret C, Debackere K, Mazzone M, Huang HD, Fendt SM, Ivanisevic J, Ho PC. α-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming. Nat Immunol 2017; 18(9): 985–994

[173] Wu WC, Sun HW, Chen J, OuYang HY, Yu XJ, Chen HT, Shuang ZY, Shi M, Wang Z, Zheng L. Immunosuppressive immature myeloid cell generation is controlled by glutamine metabolism in human cancer. Cancer Immunol Res 2019; 7(10): 1605–1618

[174] Leone RD, Zhao L, Englert JM, Sun IM, Oh MH, Sun IH, Arwood ML, Bettencourt IA, Patel CH, Wen J, Tam A, Blosser RL, Prchalova E, Alt J, Rais R, Slusher BS, Powell JD. Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion. Science 2019; 366(6468): 1013–1021

[175] Oh MH, Sun IH, Zhao L, Leone RD, Sun IM, Xu W, Collins SL, Tam AJ, Blosser RL, Patel CH, Englert JM, Arwood ML, Wen J, Chan-Li Y, Tenora L, Majer P, Rais R, Slusher BS, Horton MR, Powell JD. Targeting glutamine metabolism enhances tumor-specific immunity by modulating suppressive myeloid cells. J Clin Invest 2020; 130(7): 3865–3884

[176] Zhao Q, Kuang DM, Wu Y, Xiao X, Li XF, Li TJ, Zheng L. Activated CD69⁺ T cells foster immune privilege by regulating IDO expression in tumor-associated macrophages. J Immunol 2012; 188(3): 1117–1124

[177] Sadik A, Somarribas Patterson LF, Öztürk S, Mohapatra SR, Panitz V, Secker PF, Pfänder P, Loth S, Salem H, Prentzell MT, Berdel B, Iskar M, Faessler E, Reuter F, Kirst I, Kalter V, Foerster KI, Jäger E, Guevara CR, Sobeh M, Hielscher T, Poschet G, Reinhardt A, Hassel JC, Zapatka M, Hahn U, von Deimling A, Hopf C, Schlichting R, Escher BI, Burhenne J, Haefeli WE, Ishaque N, Böhme A, Schäuble S, Thedieck K, Trump S, Seiffert M, Opitz CA. IL4I1 is a metabolic immune checkpoint that activates the AHR and promotes tumor progression. Cell 2020; 182(5): 1252–1270.e34

[178] Bod L, Lengagne R, Wrobel L, Ramspott JP, Kato M, Avril MF, Castellano F, Molinier-Frenkel V, Prévost-Blondel A. IL4-induced gene 1 promotes tumor growth by shaping the immune microenvironment in melanoma. OncoImmunology 2017; 6(3): e1278331

[179] Mulder K, Patel AA, Kong WT, Piot C, Halitzki E, Dunsmore G, Khalilnezhad S, Irac SE, Dubuisson A, Chevrier M, Zhang XM, Tam JKC, Lim TKH, Wong RMM, Pai R, Khalil AIS, Chow PKH, Wu SZ, Al-Eryani G, Roden D, Swarbrick A, Chan JKY, Albani S, Derosa L, Zitvogel L, Sharma A, Chen J, Silvin A, Bertoletti A, Blériot C, Dutertre CA, Ginhoux F. Cross-tissue single-cell landscape of human monocytes and macrophages in health and disease. Immunity 2021; 54(8): 1883–1900.e5

[180] Pagano E, Elias JE, Schneditz G, Saveljeva S, Holland LM, Borrelli F, Karlsen TH, Kaser A, Kaneider NC. Activation of the GPR35 pathway drives angiogenesis in the tumour microenvironment. Gut 2022; 71(3): 509–520

[181] Li F, Zhao Y, Wei L, Li S, Liu J. Tumor-infiltrating Treg, MDSC, and IDO expression associated with outcomes of neoadjuvant chemotherapy of breast cancer. Cancer Biol Ther 2018; 19(8): 695–705

[182] Nandre R, Verma V, Gaur P, Patil V, Yang X, Ramlaoui Z, Shobaki N, Andersen MH, Pedersen AW, Zocca MB, Mkrtichyan M, Gupta S, Khleif SN. IDO vaccine ablates immune-suppressive myeloid populations and enhances antitumor effects independent of tumor cell IDO status. Cancer Immunol Res. 2022; 10(5): 571–580

[183] Mitchell TC, Hamid O, Smith DC, Bauer TM, Wasser JS, Olszanski AJ, Luke JJ, Balmanoukian AS, Schmidt EV, Zhao Y, Gong X, Maleski J, Leopold L, Gajewski TF. Epacadostat plus pembrolizumab in patients with advanced solid tumors: phase I results from a multicenter, open-label phase I/II trial (ECHO-202/KEYNOTE-037). J Clin Oncol 2018; 36(32): 3223–3230

[184] Mariotti V, Han H, Ismail-Khan R, Tang SC, Dillon P, Montero AJ, Poklepovic A, Melin S, Ibrahim NK, Kennedy E, Vahanian N, Link C, Tennant L, Schuster S, Smith C, Danciu O, Gilman P, Soliman H. Effect of taxane chemotherapy with or without indoximod in metastatic breast cancer: a randomized clinical trial. JAMA Oncol 2021; 7(1): 61–69

[185] Long GV, Dummer R, Hamid O, Gajewski TF, Caglevic C, Dalle S, Arance A, Carlino MS, Grob JJ, Kim TM, Demidov L, Robert C, Larkin J, Anderson JR, Maleski J, Jones M, Diede SJ, Mitchell TC. 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 2019; 20(8): 1083–1097

[186] Nagarsheth N, Wicha MS, Zou W. Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Nat Rev Immunol 2017; 17(9): 559–572

[187] Patel AA, Zhang Y, Fullerton JN, Boelen L, Rongvaux A, Maini AA, Bigley V, Flavell RA, Gilroy DW, Asquith B, Macallan D, Yona S. The fate and lifespan of human monocyte subsets in steady state and systemic inflammation. J Exp Med 2017; 214(7): 1913–1923

[188] Chen J, Ji K, Gu L, Fang Y, Pan M, Tian S. HMGA1 promotes macrophage recruitment via activation of NF-κB-CCL2 signaling in hepatocellular carcinoma. J Immunol Res 2022; 2022: 4727198

[189] Li X, Yao W, Yuan Y, Chen P, Li B, Li J, Chu R, Song H, Xie D, Jiang X, Wang H. Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma. Gut 2017; 66(1): 157–167

[190] Wang YF, Yu L, Hu Z, Fang Y, Shen Y, Song M, Chen Y. Regulation of CCL2 by EZH2 affects tumor-associated macrophages polarization and infiltration in breast cancer. Cell Death Dis 2022; 13(8): 748

[191] Tu W, Gong J, Zhou Z, Tian D, Wang Z. TCF4 enhances hepatic metastasis of colorectal cancer by regulating tumor-associated macrophage via CCL2/CCR2 signaling. Cell Death Dis 2021; 12(10): 882

[192] Yao W, Ba Q, Li X, Li H, Zhang S, Yuan Y, Wang F, Duan X, Li J, Zhang W, Wang H. A natural CCR2 antagonist relieves tumor-associated macrophage-mediated immunosuppression to produce a therapeutic effect for liver cancer. EBioMedicine 2017; 22: 58–67

[193] Cho HR, Kumari N, Thi Vu H, Kim H, Park CK, Choi SH. Increased antiangiogenic effect by blocking CCL2-dependent macrophages in a rodent glioblastoma model: correlation study with dynamic susceptibility contrast perfusion MRI. Sci Rep 2019; 9(1): 11085

[194] Teng KY, Han J, Zhang X, Hsu SH, He S, Wani NA, Barajas JM, Snyder LA, Frankel WL, Caligiuri MA, Jacob ST, Yu J, Ghoshal K. Blocking the CCL2–CCR2 axis using CCL2-neutralizing antibody is an effective therapy for hepatocellular cancer in a mouse model. Mol Cancer Ther 2017; 16(2): 312–322

[195] Tu MM, Abdel-Hafiz HA, Jones RT, Jean A, Hoff KJ, Duex JE, Chauca-Diaz A, Costello JC, Dancik GM, Tamburini BAJ, Czerniak B, Kaye J, Theodorescu D. Inhibition of the CCL2 receptor, CCR2, enhances tumor response to immune checkpoint therapy. Commun Biol 2020; 3(1): 720

[196] Chang AL, Miska J, Wainwright DA, Dey M, Rivetta CV, Yu D, Kanojia D, Pituch KC, Qiao J, Pytel P, Han Y, Wu M, Zhang L, Horbinski CM, Ahmed AU, Lesniak MS. CCL2 produced by the glioma microenvironment is essential for the recruitment of regulatory T cells and myeloid-derived suppressor cells. Cancer Res 2016; 76(19): 5671–5682

[197] Hale M, Itani F, Buchta CM, Wald G, Bing M, Norian LA. Obesity triggers enhanced MDSC accumulation in murine renal tumors via elevated local production of CCL2. PLoS One 2015; 10(3): e0118784

[198] Liang H, Deng L, Hou Y, Meng X, Huang X, Rao E, Zheng W, Mauceri H, Mack M, Xu M, Fu YX, Weichselbaum RR. Host STING-dependent MDSC mobilization drives extrinsic radiation resistance. Nat Commun 2017; 8(1): 1736

[199] Chun E, Lavoie S, Michaud M, Gallini CA, Kim J, Soucy G, Odze R, Glickman JN, Garrett WS. CCL2 promotes colorectal carcinogenesis by enhancing polymorphonuclear myeloid-derived suppressor cell population and function. Cell Rep 2015; 12(2): 244–257

[200] Liu Q, Li A, Tian Y, Wu JD, Liu Y, Li T, Chen Y, Han X, Wu K. The CXCL8-CXCR1/2 pathways in cancer. Cytokine Growth Factor Rev 2016; 31: 61–71

[201] Steele CW, Karim SA, Leach JDG, Bailey P, Upstill-Goddard R, Rishi L, Foth M, Bryson S, McDaid K, Wilson Z, Eberlein C, Candido JB, Clarke M, Nixon C, Connelly J, Jamieson N, Carter CR, Balkwill F, Chang DK, Evans TRJ, Strathdee D, Biankin AV, Nibbs RJB, Barry ST, Sansom OJ, Morton JP. CXCR2 inhibition profoundly suppresses metastases and augments immunotherapy in pancreatic ductal adenocarcinoma. Cancer Cell 2016; 29(6): 832–845

[202] Han ZJ, Li YB, Yang LX, Cheng HJ, Liu X, Chen H. Roles of the CXCL8-CXCR1/2 Axis in the tumor microenvironment and immunotherapy. Molecules 2021; 27(1): 137

[203] Jin L, Tao H, Karachi A, Long Y, Hou AY, Na M, Dyson KA, Grippin AJ, Deleyrolle LP, Zhang W, Rajon DA, Wang QJ, Yang JC, Kresak JL, Sayour EJ, Rahman M, Bova FJ, Lin Z, Mitchell DA, Huang J. CXCR1- or CXCR2-modified CAR T cells co-opt IL-8 for maximal antitumor efficacy in solid tumors. Nat Commun 2019; 10(1): 4016

[204] Halama N, Zoernig I, Berthel A, Kahlert C, Klupp F, Suarez-Carmona M, Suetterlin T, Brand K, Krauss J, Lasitschka F, Lerchl T, Luckner-Minden C, Ulrich A, Koch M, Weitz J, Schneider M, Buechler MW, Zitvogel L, Herrmann T, Benner A, Kunz C, Luecke S, Springfeld C, Grabe N, Falk CS, Jaeger D. Tumoral immune cell exploitation in colorectal cancer metastases can be targeted effectively by anti-CCR5 therapy in cancer patients. Cancer Cell 2016; 29(4): 587–601

[205] Castellino F, Huang AY, Altan-Bonnet G, Stoll S, Scheinecker C, Germain RN. Chemokines enhance immunity by guiding naive CD8⁺ T cells to sites of CD4⁺ T cell-dendritic cell interaction. Nature 2006; 440(7086): 890–895

[206] Galeano Niño JL, Pageon SV, Tay SS, Colakoglu F, Kempe D, Hywood J, Mazalo JK, Cremasco J, Govendir MA, Dagley LF, Hsu K, Rizzetto S, Zieba J, Rice G, Prior V, O’Neill GM, Williams RJ, Nisbet DR, Kramer B, Webb AI, Luciani F, Read MN, Biro M. Cytotoxic T cells swarm by homotypic chemokine signalling. eLife 2020; 9: e56554

[207] He Q, Liu M, Huang W, Chen X, Zhang B, Zhang T, Wang Y, Liu D, Xie M, Ji X, Sun M, Tian D, Xia L. IL-1β-induced elevation of solute carrier family 7 member 11 promotes hepatocellular carcinoma metastasis through up-regulating programmed death ligand 1 and colony-stimulating factor 1. Hepatology 2021; 74(6): 3174–3193

[208] Sierra-Filardi E, Nieto C, Domínguez-Soto Á, Barroso R, Sánchez-Mateos P, Puig-Kroger A, López-Bravo M, Joven J, Ardavín C, Rodríguez-Fernández JL, Sánchez-Torres C, Mellado M, Corbí ÁL. CCL2 shapes macrophage polarization by GM-CSF and M-CSF: identification of CCL2/CCR2-dependent gene expression profile. J Immunol 2014; 192(8): 3858–3867

[209] Dai XM, Ryan GR, Hapel AJ, Dominguez MG, Russell RG, Kapp S, Sylvestre V, Stanley ER. Targeted disruption of the mouse colony-stimulating factor 1 receptor gene results in osteopetrosis, mononuclear phagocyte deficiency, increased primitive progenitor cell frequencies, and reproductive defects. Blood 2002; 99(1): 111–120

[210] Wang Y, Szretter KJ, Vermi W, Gilfillan S, Rossini C, Cella M, Barrow AD, Diamond MS, Colonna M. IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia. Nat Immunol 2012; 13(8): 753–760

[211] Ries CH, Cannarile MA, Hoves S, Benz J, Wartha K, Runza V, Rey-Giraud F, Pradel LP, Feuerhake F, Klaman I, Jones T, Jucknischke U, Scheiblich S, Kaluza K, Gorr IH, Walz A, Abiraj K, Cassier PA, Sica A, Gomez-Roca C, de Visser KE, Italiano A, Le Tourneau C, Delord JP, Levitsky H, Blay JY, Rüttinger D. Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. Cancer Cell 2014; 25(6): 846–859

[212] Wiehagen KR, Girgis NM, Yamada DH, Smith AA, Chan SR, Grewal IS, Quigley M, Verona RI. Combination of CD40 agonism and CSF-1R blockade reconditions tumor-associated macrophages and drives potent antitumor immunity. Cancer Immunol Res 2017; 5(12): 1109–1121

[213] Neubert NJ, Schmittnaegel M, Bordry N, Nassiri S, Wald N, Martignier C, Tillé L, Homicsko K, Damsky W, Maby-El Hajjami H, Klaman I, Danenberg E, Ioannidou K, Kandalaft L, Coukos G, Hoves S, Ries CH, Fuertes Marraco SA, Foukas PG, De Palma M, Speiser DE. T cell-induced CSF1 promotes melanoma resistance to PD1 blockade. Sci Transl Med 2018; 10(436): eaan3311

[214] Zhu Y, Knolhoff BL, Meyer MA, Nywening TM, West BL, Luo J, Wang-Gillam A, Goedegebuure SP, Linehan DC, DeNardo DG. CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res 2014; 74(18): 5057–5069

[215] Mok S, Koya RC, Tsui C, Xu J, Robert L, Wu L, Graeber TG, West BL, Bollag G, Ribas A. Inhibition of CSF-1 receptor improves the antitumor efficacy of adoptive cell transfer immunotherapy. Cancer Res 2014; 74(1): 153–161

[216] Ruffolo LI, Jackson KM, Kuhlers PC, Dale BS, Figueroa Guilliani NM, Ullman NA, Burchard PR, Qin SS, Juviler PG, Keilson JM, Morrison AB, Georger M, Jewell R, Calvi LM, Nywening TM, O’Dell MR, Hezel AF, De Las Casas L, Lesinski GB, Yeh JJ, Hernandez-Alejandro R, Belt BA, Linehan DC. GM-CSF drives myelopoiesis, recruitment and polarisation of tumour-associated macrophages in cholangiocarcinoma and systemic blockade facilitates antitumour immunity. Gut 2022; 71(7): 1386–1398

[217] Ning WR, Jiang D, Liu XC, Huang YF, Peng ZP, Jiang ZZ, Kang T, Zhuang SM, Wu Y, Zheng L. Carbonic anhydrase XII mediates the survival and prometastatic functions of macrophages in human hepatocellular carcinoma. J Clin Invest 2022; 132(7): e153110

[218] Wang Y, Chen W, Qiao S, Zou H, Yu X, Yang Y, Li Z, Wang J, Chen M, Xu J, Zheng L. Lipid droplet accumulation mediates macrophage survival and Treg recruitment via the CCL20/CCR6 axis in human hepatocellular carcinoma. Cell Mol Immunol 2024; 21(10): 1120–1130

[219] Zhao X, Rong L, Zhao X, Li X, Liu X, Deng J, Wu H, Xu X, Erben U, Wu P, Syrbe U, Sieper J, Qin Z. TNF signaling drives myeloid-derived suppressor cell accumulation. J Clin Invest 2012; 122(11): 4094–4104

[220] Thevenot PT, Sierra RA, Raber PL, Al-Khami AA, Trillo-Tinoco J, Zarreii P, Ochoa AC, Cui Y, Del Valle L, Rodriguez PC. The stress-response sensor chop regulates the function and accumulation of myeloid-derived suppressor cells in tumors. Immunity 2014; 41(3): 389–401

[221] Condamine T, Kumar V, Ramachandran IR, Youn JI, Celis E, Finnberg N, El-Deiry WS, Winograd R, Vonderheide RH, English NR, Knight SC, Yagita H, McCaffrey JC, Antonia S, Hockstein N, Witt R, Masters G, Bauer T, Gabrilovich DI. ER stress regulates myeloid-derived suppressor cell fate through TRAIL-R-mediated apoptosis. J Clin Invest 2014; 124(6): 2626–2639

[222] Dominguez GA, Condamine T, Mony S, Hashimoto A, Wang F, Liu Q, Forero A, Bendell J, Witt R, Hockstein N, Kumar P, Gabrilovich DI. Selective targeting of myeloid-derived suppressor cells in cancer patients using DS-8273a, an agonistic TRAIL-R2 antibody. Clin Cancer Res 2017; 23(12): 2942–2950

[223] Parker KH, Horn LA, Ostrand-Rosenberg S. High-mobility group box protein 1 promotes the survival of myeloid-derived suppressor cells by inducing autophagy. J Leukoc Biol 2016; 100(3): 463–470

[224] Wang J, Wang Y, Chu Y, Li Z, Yu X, Huang Z, Xu J, Zheng L. Tumor-derived adenosine promotes macrophage proliferation in human hepatocellular carcinoma. J Hepatol 2021; 74(3): 627–637

[225] Hartley GP, Chow L, Ammons DT, Wheat WH, Dow SW. Programmed cell death ligand 1 (PD-L1) signaling regulates macrophage proliferation and activation. Cancer Immunol Res 2018; 6(10): 1260–1273

[226] Cai Z, Li W, Hager S, Wilson JL, Afjehi-Sadat L, Heiss EH, Weichhart T, Heffeter P, Weckwerth W. Targeting PHGDH reverses the immunosuppressive phenotype of tumor-associated macrophages through alpha-ketoglutarate and mTORC1 signaling. Cell Mol Immunol 2024; 21(5): 448–465

[227] Condamine T, Mastio J, Gabrilovich DI. Transcriptional regulation of myeloid-derived suppressor cells. J Leukoc Biol 2015; 98(6): 913–922

[228] Welte T, Kim IS, Tian L, Gao X, Wang H, Li J, Holdman XB, Herschkowitz JI, Pond A, Xie G, Kurley S, Nguyen T, Liao L, Dobrolecki LE, Pang L, Mo Q, Edwards DP, Huang S, Xin L, Xu J, Li Y, Lewis MT, Wang T, Westbrook TF, Rosen JM, Zhang XHF. Oncogenic mTOR signalling recruits myeloid-derived suppressor cells to promote tumour initiation. Nat Cell Biol 2016; 18(6): 632–644

[229] Gabrilovich D, Ishida T, Oyama T, Ran S, Kravtsov V, Nadaf S, Carbone DP. Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood 1998; 92(11): 4150–4166

[230] Gabrilovich DI, Chen HL, Girgis KR, Cunningham HT, Meny GM, Nadaf S, Kavanaugh D, Carbone DP. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med 1996; 2(10): 1096–1103

[231] Rivera LB, Bergers G. Intertwined regulation of angiogenesis and immunity by myeloid cells. Trends Immunol 2015; 36(4): 240–249

[232] Cheng P, Corzo CA, Luetteke N, Yu B, Nagaraj S, Bui MM, Ortiz M, Nacken W, Sorg C, Vogl T, Roth J, Gabrilovich DI. Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein. J Exp Med 2008; 205(10): 2235–2249

[233] Wu L, Yan C, Czader M, Foreman O, Blum JS, Kapur R, Du H. Inhibition of PPARγ in myeloid-lineage cells induces systemic inflammation, immunosuppression, and tumorigenesis. Blood 2012; 119(1): 115–126

[234] Oh K, Lee OY, Shon SY, Nam O, Ryu PM, Seo MW, Lee DS. A mutual activation loop between breast cancer cells and myeloid-derived suppressor cells facilitates spontaneous metastasis through IL-6 trans-signaling in a murine model. Breast Cancer Res 2013; 15(5): R79

[235] Wu WC, Sun HW, Chen HT, Liang J, Yu XJ, Wu C, Wang Z, Zheng L. Circulating hematopoietic stem and progenitor cells are myeloid-biased in cancer patients. Proc Natl Acad Sci USA 2014; 111(11): 4221–4226

[236] Cortez-Retamozo V, Etzrodt M, Newton A, Rauch PJ, Chudnovskiy A, Berger C, Ryan RJH, Iwamoto Y, Marinelli B, Gorbatov R, Forghani R, Novobrantseva TI, Koteliansky V, Figueiredo JL, Chen JW, Anderson DG, Nahrendorf M, Swirski FK, Weissleder R, Pittet MJ. Origins of tumor-associated macrophages and neutrophils. Proc Natl Acad Sci USA 2012; 109(7): 2491–2496

[237] Casbon AJ, Reynaud D, Park C, Khuc E, Gan DD, Schepers K, Passegué E, Werb Z. Invasive breast cancer reprograms early myeloid differentiation in the bone marrow to generate immunosuppressive neutrophils. Proc Natl Acad Sci USA 2015; 112(6): E566–E575

[238] Wu C, Ning H, Liu M, Lin J, Luo S, Zhu W, Xu J, Wu WC, Liang J, Shao CK, Ren J, Wei B, Cui J, Chen MS, Zheng L. Spleen mediates a distinct hematopoietic progenitor response supporting tumor-promoting myelopoiesis. J Clin Invest 2018; 128(8): 3425–3438

[239] Ugel S, Peranzoni E, Desantis G, Chioda M, Walter S, Weinschenk T, Ochando JC, Cabrelle A, Mandruzzato S, Bronte V. Immune tolerance to tumor antigens occurs in a specialized environment of the spleen. Cell Rep 2012; 2(3): 628–639

[240] Almand B, Clark JI, Nikitina E, van Beynen J, English NR, Knight SC, Carbone DP, Gabrilovich DI. Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. J Immunol 2001; 166(1): 678–689

[241] Bronte V, Apolloni E, Cabrelle A, Ronca R, Serafini P, Zamboni P, Restifo NP, Zanovello P. Identification of a CD11b⁺/Gr-1⁺/CD31⁺ myeloid progenitor capable of activating or suppressing CD8⁺ T cells. Blood 2000; 96(12): 3838–3846

[242] Marigo I, Bosio E, Solito S, Mesa C, Fernandez A, Dolcetti L, Ugel S, Sonda N, Bicciato S, Falisi E, Calabrese F, Basso G, Zanovello P, Cozzi E, Mandruzzato S, Bronte V. Tumor-induced tolerance and immune suppression depend on the C/EBPβ transcription factor. Immunity 2010; 32(6): 790–802

[243] Cortez-Retamozo V, Etzrodt M, Newton A, Ryan R, Pucci F, Sio SW, Kuswanto W, Rauch PJ, Chudnovskiy A, Iwamoto Y, Kohler R, Marinelli B, Gorbatov R, Wojtkiewicz G, Panizzi P, Mino-Kenudson M, Forghani R, Figueiredo JL, Chen JW, Xavier R, Swirski FK, Nahrendorf M, Weissleder R, Pittet MJ. Angiotensin II drives the production of tumor-promoting macrophages. Immunity 2013; 38(2): 296–308

[244] Bronte V, Pittet MJ. The spleen in local and systemic regulation of immunity. Immunity 2013; 39(5): 806–818

[245] Long H, Jia Q, Wang L, Fang W, Wang Z, Jiang T, Zhou F, Jin Z, Huang J, Zhou L, Hu C, Wang X, Zhang J, Ba Y, Gong Y, Zeng X, Zeng D, Su X, Alexander PB, Wang L, Wang L, Wan YY, Wang XF, Zhang L, Li QJ, Zhu B. Tumor-induced erythroid precursor-differentiated myeloid cells mediate immunosuppression and curtail anti-PD-1/PD-L1 treatment efficacy. Cancer Cell 2022; 40(6): 674–693.e7

[246] Zhao L, He R, Long H, Guo B, Jia Q, Qin D, Liu SQ, Wang Z, Xiang T, Zhang J, Tan Y, Huang J, Chen J, Wang F, Xiao M, Gao J, Yang X, Zeng H, Wang X, Hu C, Alexander PB, Symonds ALJ, Yu J, Wan Y, Li QJ, Ye L, Zhu B. Late-stage tumors induce anemia and immunosuppressive extramedullary erythroid progenitor cells. Nat Med 2018; 24(10): 1536–1544

[247] Han Y, Liu Q, Hou J, Gu Y, Zhang Y, Chen Z, Fan J, Zhou W, Qiu S, Zhang Y, Dong T, Li N, Jiang Z, Zhu H, Zhang Q, Ma Y, Zhang L, Wang Q, Yu Y, Li N, Cao X. Tumor-induced generation of splenic erythroblast-like Ter-cells promotes tumor progression. Cell 2018; 173(3): 634–648.e12

[248] Cannarile MA, Weisser M, Jacob W, Jegg AM, Ries CH, Rüttinger D. Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy. J Immunother Cancer 2017; 5(1): 53

[249] Chaib M, Chauhan SC, Makowski L. Friend or foe? Recent strategies to target myeloid cells in cancer. Front Cell Dev Biol 2020; 8: 351

[250] Jahchan NS, Mujal AM, Pollack JL, Binnewies M, Sriram V, Reyno L, Krummel MF. Tuning the tumor myeloid microenvironment to fight cancer. Front Immunol 2019; 10: 1611

[251] Mitchem JB, Brennan DJ, Knolhoff BL, Belt BA, Zhu Y, Sanford DE, Belaygorod L, Carpenter D, Collins L, Piwnica-Worms D, Hewitt S, Udupi GM, Gallagher WM, Wegner C, West BL, Wang-Gillam A, Goedegebuure P, Linehan DC, DeNardo DG. Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses. Cancer Res 2013; 73(3): 1128–1141

[252] Kalbasi A, Komar C, Tooker GM, Liu M, Lee JW, Gladney WL, Ben-Josef E, Beatty GL. Tumor-derived CCL2 mediates resistance to radiotherapy in pancreatic ductal adenocarcinoma. Clin Cancer Res 2017; 23(1): 137–148

[253] Connolly KA, Belt BA, Figueroa NM, Murthy A, Patel A, Kim M, Lord EM, Linehan DC, Gerber SA. Increasing the efficacy of radiotherapy by modulating the CCR2/CCR5 chemokine axes. Oncotarget 2016; 7(52): 86522–86535

[254] Fridlender ZG, Buchlis G, Kapoor V, Cheng G, Sun J, Singhal S, Crisanti MC, Wang LCS, Heitjan D, Snyder LA, Albelda SM. CCL2 blockade augments cancer immunotherapy. Cancer Res 2010; 70(1): 109–118

[255] Flores-Toro JA, Luo D, Gopinath A, Sarkisian MR, Campbell JJ, Charo IF, Singh R, Schall TJ, Datta M, Jain RK, Mitchell DA, Harrison JK. CCR2 inhibition reduces tumor myeloid cells and unmasks a checkpoint inhibitor effect to slow progression of resistant murine gliomas. Proc Natl Acad Sci USA 2020; 117(2): 1129–1138

[256] Zhu Y, Herndon JM, Sojka DK, Kim KW, Knolhoff BL, Zuo C, Cullinan DR, Luo J, Bearden AR, Lavine KJ, Yokoyama WM, Hawkins WG, Fields RC, Randolph GJ, DeNardo DG. Tissue-resident macrophages in pancreatic ductal adenocarcinoma originate from embryonic hematopoiesis and promote tumor progression. Immunity. 2017; 47(2): 323–338.e6

[257] 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): 1112–1123

[258] Papadopoulos KP, Gluck L, Martin LP, Olszanski AJ, Tolcher AW, Ngarmchamnanrith G, Rasmussen E, Amore BM, Nagorsen D, Hill JS, Stephenson J Jr. First-in-human study of AMG 820, a monoclonal anti-colony-stimulating factor 1 receptor antibody, in patients with advanced solid tumors. Clin Cancer Res 2017; 23(19): 5703–5710

[259] Zhang L, Li Z, Skrzypczynska KM, Fang Q, Zhang W, O'Brien SA, He Y, Wang L, Zhang Q, Kim A, Gao R, Orf J, Wang T, Sawant D, Kang J, Bhatt D, Lu D, Li CM, Rapaport AS, Perez K, Ye Y, Wang S, Hu X, Ren X, Ouyang W, Shen Z, Egen JG, Zhang Z, Yu X. Single-cell analyses inform mechanisms of myeloid-targeted therapies in colon cancer. Cell. 2020; 181(2): 442–459.e29

[260] Kumar V, Donthireddy L, Marvel D, Condamine T, Wang F, Lavilla-Alonso S, Hashimoto A, Vonteddu P, Behera R, Goins MA, Mulligan C, Nam B, Hockstein N, Denstman F, Shakamuri S, Speicher DW, Weeraratna AT, Chao T, Vonderheide RH, Languino LR, Ordentlich P, Liu Q, Xu X, Lo A, Puré E, Zhang C, Loboda A, Sepulveda MA, Snyder LA, Gabrilovich DI. Cancer-associated fibroblasts neutralize the anti-tumor effect of CSF1 receptor blockade by inducing PMN-MDSC infiltration of tumors. Cancer cell 2017; 32(5): 654–668.e5

[261] Gyori D, Lim EL, Grant FM, Spensberger D, Roychoudhuri R, Shuttleworth SJ, Okkenhaug K, Stephens LR, Hawkins PT. Compensation between CSF1R⁺ macrophages and Foxp3⁺ Treg cells drives resistance to tumor immunotherapy. JCI Insight 2018; 3(11): e120631

[262] Sun L, Clavijo PE, Robbins Y, Patel P, Friedman J, Greene S, Das R, Silvin C, Van Waes C, Horn LA, Schlom J, Palena C, Maeda D, Zebala J, Allen CT. Inhibiting myeloid-derived suppressor cell trafficking enhances T cell immunotherapy. JCI Insight 2019; 4(7): e126853

[263] Wu C, Lin J, Weng Y, Zeng DN, Xu J, Luo S, Xu L, Liu M, Hua Q, Liu CQ, Li JQ, Liao J, Sun C, Zhou J, Chen MS, Liu C, Guo Z, Zhuang SM, Huang JH, Zheng L. Myeloid signature reveals immune contexture and predicts the prognosis of hepatocellular carcinoma. J Clin Invest 2020; 130(9): 4679–4693

[264] Liu M, Wu C, Luo S, Hua Q, Chen HT, Weng Y, Xu J, Lin H, Wang L, Li J, Zhu L, Guo Z, Zhuang SM, Kang T, Zheng L. PERK reprograms hematopoietic progenitor cells to direct tumor-promoting myelopoiesis in the spleen. J Exp Med 2022; 219(4): e20211498

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