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Myeloid-derived suppressor cells in cancer and cancer therapy

Nature Reviews Clinical Oncology volume 21, pages 147–164 (2024)Cite this article

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Abstract

Anticancer agents continue to dominate the list of newly approved drugs, approximately half of which are immunotherapies. This trend illustrates the considerable promise of cancer treatments that modulate the immune system. However, the immune system is complex and dynamic, and can have both tumour-suppressive and tumour-promoting effects. Understanding the full range of immune modulation in cancer is crucial to identifying more effective treatment strategies. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of myeloid cells that develop in association with chronic inflammation, which is a hallmark of cancer. Indeed, MDSCs accumulate in the tumour microenvironment, where they strongly inhibit anticancer functions of T cells and natural killer cells and exert a variety of other tumour-promoting effects. Emerging evidence indicates that MDSCs also contribute to resistance to cancer treatments, particularly immunotherapies. Conversely, treatment approaches designed to eliminate cancer cells can have important additional effects on MDSC function, which can be either positive or negative. In this Review, we discuss the interplay between MDSCs and various other cell types found in tumours as well as the mechanisms by which MDSCs promote tumour progression. We also discuss the relevance and implications of MDSCs for cancer therapy.

Key points

  • Cancer-associated conditions, including hypoxia, nutrient deficiency, acidity, endoplasmic reticulum stress and long-term production of inflammatory mediators, promote the generation of myeloid-derived suppressor cells (MDSCs).

  • MDSCs support the progression of most cancer entities by suppressing antitumour immune responses, stimulating angiogenesis and fostering metastasis through a variety of mechanisms.

  • MDSCs contribute to primary and acquired resistance to cancer immunotherapy; thus, combinatorial therapeutic targeting of these cells might improve patient outcomes.

  • Other cancer treatments, such as chemotherapy, radiotherapy, targeted therapies or hormone therapies, can have distinct and disparate effects on MDSCs and should be studied further.

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Fig. 1: The nurturing relationship between MDSCs and tumours.
Fig. 2: Implications of MDSCs for cancer therapy.

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References

  1. Dunn, G. P., Bruce, A. T., Ikeda, H., Old, L. J. & Schreiber, R. D. Cancer immunoediting: from immunosurveillance to tumor escape. Nat. Immunol. 3, 991–998 (2002).

    Article  CAS  PubMed  Google Scholar 

  2. Condamine, T., Mastio, J. & Gabrilovich, D. I. Transcriptional regulation of myeloid-derived suppressor cells. J. Leukoc. Biol. 98, 913–922 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Hicks, K. C., Tyurina, Y. Y., Kagan, V. E. & Gabrilovich, D. I. Myeloid cell-derived oxidized lipids and regulation of the tumor microenvironment. Cancer Res. 82, 187–194 (2022).

    Article  CAS  PubMed  Google Scholar 

  4. Gabrilovich, D. I. et al. The terminology issue for myeloid-derived suppressor cells. Cancer Res. 67, 425 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Bronte, V. et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat. Commun. 7, 12150 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Mishalian, I., Granot, Z. & Fridlender, Z. G. The diversity of circulating neutrophils in cancer. Immunobiology 222, 82–88 (2017).

    Article  CAS  PubMed  Google Scholar 

  7. Hegde, S., Leader, A. M. & Merad, M. MDSC: markers, development, states, and unaddressed complexity. Immunity 54, 875–884 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Antuamwine, B. B. et al. N1 versus N2 and PMN-MDSC: a critical appraisal of current concepts on tumor-associated neutrophils and new directions for human oncology. Immunol. Rev. 314, 250–279 (2023).

    Article  CAS  PubMed  Google Scholar 

  9. Ostrand-Rosenberg, S., Lamb, T. J. & Pawelec, G. Here, there, and everywhere: myeloid-derived suppressor cells in immunology. J. Immunol. 210, 1183–1197 (2023).

    Article  CAS  PubMed  Google Scholar 

  10. Groth, C. et al. Immunosuppression mediated by myeloid-derived suppressor cells (MDSCs) during tumour progression. Br. J. Cancer 120, 16–25 (2019).

    Article  CAS  PubMed  Google Scholar 

  11. Özkan, B., Lim, H. & Park, S.-G. Immunomodulatory function of myeloid-derived suppressor cells during B cell-mediated immune responses. Int. J. Mol. Sci. 19, 1468 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Ma, T. et al. Myeloid-derived suppressor cells in solid tumors. Cells 11, 310 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Condamine, T., Ramachandran, I., Youn, J.-I. & Gabrilovich, D. I. Regulation of tumor metastasis by myeloid-derived suppressor cells. Annu. Rev. Med. 66, 97–110 (2015).

    Article  CAS  PubMed  Google Scholar 

  14. Safarzadeh, E., Orangi, M., Mohammadi, H., Babaie, F. & Baradaran, B. Myeloid-derived suppressor cells: important contributors to tumor progression and metastasis. J. Cell. Physiol. 233, 3024–3036 (2018).

    Article  CAS  PubMed  Google Scholar 

  15. Li, T. et al. Targeting MDSC for immune-checkpoint blockade in cancer immunotherapy: current progress and new prospects. Clin. Med. Insights Oncol. 15, 11795549211035540 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Bronte, V. et al. Identification of a CD11b+/Gr-1+/CD31+ myeloid progenitor capable of activating or suppressing CD8+ T cells. Blood 96, 3838–3846 (2000).

    Article  CAS  PubMed  Google Scholar 

  17. Bronte, V. et al. Apoptotic death of CD8+ T lymphocytes after immunization: induction of a suppressive population of Mac-1+/Gr-1+ cells. J. Immunol. 161, 5313–5320 (1998).

    Article  CAS  PubMed  Google Scholar 

  18. Movahedi, K. et al. Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity. Blood 111, 4233–4244 (2008).

    Article  CAS  PubMed  Google Scholar 

  19. Haile, L. A., Gamrekelashvili, J., Manns, M. P., Korangy, F. & Greten, T. F. CD49d is a new marker for distinct myeloid-derived suppressor cell subpopulations in mice. J. Immunol. 185, 203–210 (2010).

    Article  CAS  PubMed  Google Scholar 

  20. Dumitru, C. A., Moses, K., Trellakis, S., Lang, S. & Brandau, S. Neutrophils and granulocytic myeloid-derived suppressor cells: immunophenotyping, cell biology and clinical relevance in human oncology. Cancer Immunol. Immunother. 61, 1155–1167 (2012).

    Article  CAS  PubMed  Google Scholar 

  21. Mastio, J. et al. Identification of monocyte-like precursors of granulocytes in cancer as a mechanism for accumulation of PMN-MDSCs. J. Exp. Med. 216, 2150–2169 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Cheng, S. et al. A pan-cancer single-cell transcriptional atlas of tumor infiltrating myeloid cells. Cell 184, 792–809.e23 (2021).

    Article  CAS  PubMed  Google Scholar 

  23. Alshetaiwi, H. et al. Defining the emergence of myeloid-derived suppressor cells in breast cancer using single-cell transcriptomics. Sci. Immunol. 5, eaay6017 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Condamine, T. et al. Lectin-type oxidized LDL receptor-1 distinguishes population of human polymorphonuclear myeloid-derived suppressor cells in cancer patients. Sci. Immunol. 1, aaf8943 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Veglia, F., Sanseviero, E. & Gabrilovich, D. I. Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity. Nat. Rev. Immunol. 21, 485–498 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Katzenelenbogen, Y. et al. Coupled scRNA-Seq and intracellular protein activity reveal an immunosuppressive role of TREM2 in cancer. Cell 182, 872–885.e19 (2020).

    Article  CAS  PubMed  Google Scholar 

  27. Condamine, T. & Gabrilovich, D. I. Molecular mechanisms regulating myeloid-derived suppressor cell differentiation and function. Trends Immunol. 32, 19–25 (2011).

    Article  CAS  PubMed  Google Scholar 

  28. Welte, T. et al. Oncogenic mTOR signalling recruits myeloid-derived suppressor cells to promote tumour initiation. Nat. Cell Biol. 18, 632–644 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Gabrilovich, D. et al. Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood 92, 4150–4166 (1998).

    Article  CAS  PubMed  Google Scholar 

  30. Gabrilovich, D. I. et al. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat. Med. 2, 1096–1103 (1996).

    Article  CAS  PubMed  Google Scholar 

  31. Rivera, L. B. & Bergers, G. Intertwined regulation of angiogenesis and immunity by myeloid cells. Trends Immunol. 36, 240–249 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Weber, R. et al. IL-6 regulates CCR5 expression and immunosuppressive capacity of MDSC in murine melanoma. J. Immunother. Cancer 8, e000949 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Weber, R. et al. IL-6 as a major regulator of MDSC activity and possible target for cancer immunotherapy. Cell. Immunol. 359, 104254 (2021).

    Article  CAS  PubMed  Google Scholar 

  34. Corzo, C. A. et al. HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J. Exp. Med. 207, 2439–2453 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Obermajer, N., Muthuswamy, R., Lesnock, J., Edwards, R. P. & Kalinski, P. Positive feedback between PGE2 and COX2 redirects the differentiation of human dendritic cells toward stable myeloid-derived suppressor cells. Blood 118, 5498–5505 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Morello, S., Pinto, A., Blandizzi, C. & Antonioli, L. Myeloid cells in the tumor microenvironment: role of adenosine. Oncoimmunology 5, e1108515 (2016).

    Article  PubMed  Google Scholar 

  37. Fultang, N., Li, X., Li, T. & Chen, Y. H. Myeloid-derived suppressor cell differentiation in cancer: transcriptional regulators and enhanceosome-mediated mechanisms. Front. Immunol. 11, 619253 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  38. McClure, C. et al. Stat3 and C/EBPβ synergize to induce miR-21 and miR-181b expression during sepsis. Immunol. Cell Biol. 95, 42–55 (2017).

    Article  CAS  PubMed  Google Scholar 

  39. Halaby, M. J. et al. GCN2 drives macrophage and MDSC function and immunosuppression in the tumor microenvironment. Sci. Immunol. 4, eaax8189 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Yan, D. et al. TIPE2 specifies the functional polarization of myeloid-derived suppressor cells during tumorigenesis. J. Exp. Med. 217, e20182005 (2019).

    Article  PubMed Central  Google Scholar 

  41. Waight, J. D. et al. Myeloid-derived suppressor cell development is regulated by a STAT/IRF-8 axis. J. Clin. Invest. 123, 4464–4478 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Li, T. et al. c-Rel is a myeloid checkpoint for cancer immunotherapy. Nat. Cancer 1, 507–517 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Lim, H. X., Kim, T. S. & Poh, C. L. Understanding the differentiation, expansion, recruitment and suppressive activities of myeloid-derived suppressor cells in cancers. Int. J. Mol. Sci. 21, 3599 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Groth, C. et al. Blocking migration of polymorphonuclear myeloid-derived suppressor cells inhibits mouse melanoma progression. Cancers 13, 726 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Blattner, C. et al. CCR5+ myeloid-derived suppressor cells are enriched and activated in melanoma lesions. Cancer Res. 78, 157–167 (2018).

    Article  CAS  PubMed  Google Scholar 

  46. Huang, K. et al. Notch3 signaling promotes colorectal tumor growth by enhancing immunosuppressive cells infiltration in the microenvironment. BMC Cancer 23, 55 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Bitsch, R. et al. STAT3 inhibitor napabucasin abrogates MDSC immunosuppressive capacity and prolongs survival of melanoma-bearing mice. J. Immunother. Cancer 10, e004384 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Arkhypov, I. et al. Myeloid cell modulation by tumor-derived extracellular vesicles. Int. J. Mol. Sci. 21, 6319 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Xiang, X. et al. Induction of myeloid-derived suppressor cells by tumor exosomes. Int. J. Cancer 124, 2621–2633 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Condamine, T. et al. ER stress regulates myeloid-derived suppressor cell fate through TRAIL-R-mediated apoptosis. J. Clin. Invest. 124, 2626–2639 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Veglia, F. et al. Fatty acid transport protein 2 reprograms neutrophils in cancer. Nature 569, 73–78 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Pan, P.-Y. et al. Immune stimulatory receptor CD40 is required for T-cell suppression and T regulatory cell activation mediated by myeloid-derived suppressor cells in cancer. Cancer Res. 70, 99–108 (2010).

    Article  CAS  PubMed  Google Scholar 

  53. Zoso, A. et al. Human fibrocytic myeloid-derived suppressor cells express IDO and promote tolerance via Treg-cell expansion. Eur. J. Immunol. 44, 3307–3319 (2014).

    Article  CAS  PubMed  Google Scholar 

  54. Pang, B. et al. Myeloid-derived suppressor cells shift Th17/Treg ratio and promote systemic lupus erythematosus progression through arginase-1/miR-322-5p/TGF-β pathway. Clin. Sci. 134, 2209–2222 (2020).

    Article  CAS  Google Scholar 

  55. Rosser, E. C. & Mauri, C. Regulatory B cells: origin, phenotype, and function. Immunity 42, 607–612 (2015).

    Article  CAS  PubMed  Google Scholar 

  56. Lee-Chang, C. et al. Myeloid-derived suppressive cells promote B cell-mediated immunosuppression via transfer of PD-L1 in glioblastoma. Cancer Immunol. Res. 7, 1928–1943 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Bodogai, M. et al. Immunosuppressive and prometastatic functions of myeloid-derived suppressive cells rely upon education from tumor-associated B cells. Cancer Res. 75, 3456–3465 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Ostrand-Rosenberg, S., Sinha, P., Beury, D. W. & Clements, V. K. Cross-talk between myeloid-derived suppressor cells (MDSC), macrophages, and dendritic cells enhances tumor-induced immune suppression. Semin. Cancer Biol. 22, 275–281 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Gabrilovich, D. I., Ostrand-Rosenberg, S. & Bronte, V. Coordinated regulation of myeloid cells by tumours. Nat. Rev. Immunol. 12, 253–268 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Beury, D. W. et al. Cross-talk among myeloid-derived suppressor cells, macrophages, and tumor cells impacts the inflammatory milieu of solid tumors. J. Leukoc. Biol. 96, 1109–1118 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  61. van Vlerken-Ysla, L., Tyurina, Y. Y., Kagan, V. E. & Gabrilovich, D. I. Functional states of myeloid cells in cancer. Cancer Cell 41, 490–504 (2023).

    Article  PubMed  Google Scholar 

  62. Kwak, T. et al. Distinct populations of immune-suppressive macrophages differentiate from monocytic myeloid-derived suppressor cells in cancer. Cell Rep. 33, 108571 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Mantovani, A., Allavena, P., Sica, A. & Balkwill, F. Cancer-related inflammation. Nature 454, 436–444 (2008).

    Article  CAS  PubMed  Google Scholar 

  64. Beatty, P. L. et al. Immunobiology and immunosurveillance in patients with intraductal papillary mucinous neoplasms (IPMNs), premalignant precursors of pancreatic adenocarcinomas. Cancer Immunol. Immunother. 65, 771–778 (2016).

    Article  CAS  PubMed  Google Scholar 

  65. Huang, X. et al. The molecular, immune features, and risk score construction of intraductal papillary mucinous neoplasm patients. Front. Mol. Biosci. 9, 887887 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Ma, P. et al. Circulating myeloid derived suppressor cells (MDSC) that accumulate in premalignancy share phenotypic and functional characteristics with MDSC in cancer. Front. Immunol. 10, 1401 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Ding, L. et al. Schlafen 4-expressing myeloid-derived suppressor cells are induced during murine gastric metaplasia. J. Clin. Invest. 126, 2867–2880 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Ding, L. et al. Toll-like receptor 9 pathway mediates schlafen+ MDSC polarization during helicobacter-induced gastric metaplasias. Gastroenterology 163, 411–425.e4 (2022).

    Article  CAS  PubMed  Google Scholar 

  69. Zhang, X. et al. CD147 mediates epidermal malignant transformation through the RSK2/AP-1 pathway. J. Exp. Clin. Cancer Res. 41, 246 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Wang, T. et al. The adaptor protein CARD9 protects against colon cancer by restricting mycobiota-mediated expansion of myeloid-derived suppressor cells. Immunity 49, 504–514.e4 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Zhang, Q. et al. Gut microbiome directs hepatocytes to recruit MDSCs and promote cholangiocarcinoma. Cancer Discov. 11, 1248–1267 (2021).

    Article  CAS  PubMed  Google Scholar 

  72. Harusato, A. et al. Early-life microbiota exposure restricts myeloid-derived suppressor cell-driven colonic tumorigenesis. Cancer Immunol. Res. 7, 544–551 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Campregher, C., Luciani, M. G. & Gasche, C. Activated neutrophils induce an hMSH2-dependent G2/M checkpoint arrest and replication errors at a (CA)13-repeat in colon epithelial cells. Gut 57, 780 (2008).

    Article  CAS  PubMed  Google Scholar 

  74. Ibrahim, M. L. et al. Myeloid-derived suppressor cells produce IL-10 to elicit DNMT3b-dependent IRF8 silencing to promote colitis-associated colon tumorigenesis. Cell Rep. 25, 3036–3046.e6 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Grivennikov, S. et al. IL-6 and STAT3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 15, 103–113 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Ke, Z. et al. PAR2 deficiency enhances myeloid cell-mediated immunosuppression and promotes colitis-associated tumorigenesis. Cancer Lett. 469, 437–446 (2020).

    Article  CAS  PubMed  Google Scholar 

  77. Tang, C. et al. Blocking Dectin-1 prevents colorectal tumorigenesis by suppressing prostaglandin E2 production in myeloid-derived suppressor cells and enhancing IL-22 binding protein expression. Nat. Commun. 14, 1493 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Chen, X. et al. Induction of myelodysplasia by myeloid-derived suppressor cells. J. Clin. Invest. 123, 4595–4611 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Seliger, B. Strategies of tumor immune evasion. BioDrugs 19, 347–354 (2005).

    Article  CAS  PubMed  Google Scholar 

  80. Vinay, D. S. et al. Immune evasion in cancer: mechanistic basis and therapeutic strategies. Semin. Cancer Biol. 35, S185–S198 (2015).

    Article  PubMed  Google Scholar 

  81. Hsu, J. et al. Contribution of NK cells to immunotherapy mediated by PD-1/PD-L1 blockade. J. Clin. Invest. 128, 4654–4668 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Sun, R. et al. Tumor-associated neutrophils suppress antitumor immunity of NK cells through the PD-L1/PD-1 axis. Transl. Oncol. 13, 100825 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Christiansson, L. et al. Increased level of myeloid-derived suppressor cells, programmed death receptor ligand 1/programmed death receptor 1, and soluble CD25 in Sokal high risk chronic myeloid leukemia. PLoS ONE 8, e55818 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Zhang, B. et al. Circulating and tumor-infiltrating myeloid-derived suppressor cells in patients with colorectal carcinoma. PLoS ONE 8, e57114 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Duraiswamy, J., Freeman, G. J. & Coukos, G. Therapeutic PD-1 pathway blockade augments with other modalities of immunotherapy T-cell function to prevent immune decline in ovarian cancer. Cancer Res. 73, 6900–6912 (2013).

    Article  CAS  PubMed  Google Scholar 

  86. Noman, M. Z. et al. PD-L1 is a novel direct target of HIF-1alpha, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J. Exp. Med. 211, 781–790 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Iwata, T. et al. PD-L1+MDSCs are increased in HCC patients and induced by soluble factor in the tumor microenvironment. Sci. Rep. 6, 39296 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Prima, V., Kaliberova, L. N., Kaliberov, S., Curiel, D. T. & Kusmartsev, S. COX2/mPGES1/PGE2 pathway regulates PD-L1 expression in tumor-associated macrophages and myeloid-derived suppressor cells. Proc. Natl Acad. Sci. USA 114, 1117–1122 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Fleming, V. et al. Melanoma extracellular vesicles generate immunosuppressive myeloid cells by upregulating PD-L1 via TLR4 signaling. Cancer Res. 79, 4715–4728 (2019).

    Article  CAS  PubMed  Google Scholar 

  90. Filipazzi, P., Bürdek, M., Villa, A., Rivoltini, L. & Huber, V. Recent advances on the role of tumor exosomes in immunosuppression and disease progression. Semin. Cancer Biol. 22, 342–349 (2012).

    Article  CAS  PubMed  Google Scholar 

  91. Valenti, R. et al. Human tumor-released microvesicles promote the differentiation of myeloid cells with transforming growth factor-β-mediated suppressive activity on T lymphocytes. Cancer Res. 66, 9290–9298 (2006).

    Article  CAS  PubMed  Google Scholar 

  92. Valenti, R. et al. Tumor-released microvesicles as vehicles of immunosuppression. Cancer Res. 67, 2912–2915 (2007).

    Article  CAS  PubMed  Google Scholar 

  93. Strauss, L. et al. Targeted deletion of PD-1 in myeloid cells induces antitumor immunity. Sci. Immunol. 5, eaay1863 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Rodriguez, P. C., Quiceno, D. G. & Ochoa, A. C. L-arginine availability regulates T-lymphocyte cell-cycle progression. Blood 109, 1568–1573 (2006).

    Article  PubMed  Google Scholar 

  95. Rodriguez, P. C. et al. Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses. Cancer Res. 64, 5839–5849 (2004).

    Article  CAS  PubMed  Google Scholar 

  96. Grzywa, T. M. et al. Myeloid cell-derived arginase in cancer immune response. Front. Immunol. 11, 938 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Youn, J.-I., Collazo, M., Shalova, I. N., Biswas, S. K. & Gabrilovich, D. I. Characterization of the nature of granulocytic myeloid-derived suppressor cells in tumor-bearing mice. J. Leukoc. Biol. 91, 167–181 (2011).

    Article  PubMed  Google Scholar 

  98. Baumann, T. et al. Regulatory myeloid cells paralyze T cells through cell–cell transfer of the metabolite methylglyoxal. Nat. Immunol. 21, 555–566 (2020).

    Article  CAS  PubMed  Google Scholar 

  99. Srivastava, M. K., Sinha, P., Clements, V. K., Rodriguez, P. & Ostrand-Rosenberg, S. Myeloid-derived suppressor cells inhibit T-cell activation by depleting cystine and cysteine. Cancer Res. 70, 68–77 (2010).

    Article  CAS  PubMed  Google Scholar 

  100. Yu, J. et al. Myeloid-derived suppressor cells suppress antitumor immune responses through IDO expression and correlate with lymph node metastasis in patients with breast cancer. J. Immunol. 190, 3783–3797 (2013).

    Article  CAS  PubMed  Google Scholar 

  101. Bilir, C. & Sarisozen, C. Indoleamine 2,3-dioxygenase (IDO): only an enzyme or a checkpoint controller? J. Oncol. Sci. 3, 52–56 (2017).

    Article  Google Scholar 

  102. Frumento, G. et al. Tryptophan-derived catabolites are responsible for inhibition of t and natural killer cell proliferation induced by indoleamine 2,3-dioxygenase. J. Exp. Med. 196, 459–468 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Munn, D. H. et al. GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Immunity 22, 633–642 (2005).

    Article  CAS  PubMed  Google Scholar 

  104. Mezrich, J. D. et al. An Interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J. Immunol. 185, 3190–3198 (2010).

    Article  CAS  PubMed  Google Scholar 

  105. Chiesa, M. D. et al. The tryptophan catabolite l-kynurenine inhibits the surface expression of NKp46- and NKG2D-activating receptors and regulates NK-cell function. Blood 108, 4118–4125 (2006).

    Article  PubMed  Google Scholar 

  106. Corzo, C. A. et al. Mechanism regulating reactive oxygen species in tumor-induced myeloid-derived suppressor cells. J. Immunol. 182, 5693–5701 (2009).

    Article  CAS  PubMed  Google Scholar 

  107. Fiaschi, T. & Chiarugi, P. Oxidative stress, tumor microenvironment, and metabolic reprogramming: a diabolic liaison. Int. J. Cell Biol. 2012, 762825 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  108. Nagaraj, S. et al. Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer. Nat. Med. 13, 828–835 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Feng, S. et al. Myeloid-derived suppressor cells inhibit T cell activation through nitrating LCK in mouse cancers. Proc. Natl Acad. Sci. USA 115, 10094–10099 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Bingisser, R. M., Tilbrook, P. A., Holt, P. G. & Kees, U. R. Macrophage-derived nitric oxide regulates T cell activation via reversible disruption of the Jak3/STAT5 signaling pathway. J. Immunol. 160, 5729–5734 (1998).

    Article  CAS  PubMed  Google Scholar 

  111. Wang, Z. et al. A myeloid cell population induced by Freund adjuvant suppresses T-cell-mediated antitumor immunity. J. Immunother. 33, 167–177 (2010).

    Article  PubMed  Google Scholar 

  112. Gehad, A. E. et al. Nitric oxide-producing myeloid-derived suppressor cells inhibit vascular E-selectin expression in human squamous cell carcinomas. J. Invest. Dermatol. 132, 2642–2651 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Molon, B. et al. Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells. J. Exp. Med. 208, 1949–1962 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Stiff, A. et al. Nitric oxide production by myeloid-derived suppressor cells plays a role in impairing Fc receptor-mediated natural killer cell function. Clin. Cancer Res. 24, 1891–1904 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Tcyganov, E. N. et al. Peroxynitrite in the tumor microenvironment changes the profile of antigens allowing escape from cancer immunotherapy. Cancer Cell 40, 1173–1189.e6 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Li, J. et al. CD39/CD73 upregulation on myeloid-derived suppressor cells via TGF-β-mTOR-HIF-1 signaling in patients with non-small cell lung cancer. Oncoimmunology 6, e1320011 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  117. Hanson, E. M., Clements, V. K., Sinha, P., Ilkovitch, D. & Ostrand-Rosenberg, S. Myeloid-derived suppressor cells down-regulate L-selectin expression on CD4+ and CD8+ T cells. J. Immunol. 183, 937–944 (2009).

    Article  CAS  PubMed  Google Scholar 

  118. Cozzolino, M. et al. The voltage-gated Hv1 H+ channel is expressed in tumor-infiltrating myeloid-derived suppressor cells. Int. J. Mol. Sci. 24, 6216 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Huber, V. et al. Cancer acidity: an ultimate frontier of tumor immune escape and a novel target of immunomodulation. Semin. Cancer Biol. 43, 74–89 (2017).

    Article  CAS  PubMed  Google Scholar 

  120. Kim, R. et al. Ferroptosis of tumour neutrophils causes immune suppression in cancer. Nature 612, 338–346 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Loercher, A. E., Nash, M. A., Kavanagh, J. J., Platsoucas, C. D. & Freedman, R. S. Identification of an IL-10-producing HLA-DR-negative monocyte subset in the malignant ascites of patients with ovarian carcinoma that inhibits cytokine protein expression and proliferation of autologous T cells. J. Immunol. 163, 6251–6260 (1999).

    Article  CAS  PubMed  Google Scholar 

  122. Vuk-Pavlović, S. et al. Immunosuppressive CD14+HLA-DRlow/− monocytes in prostate cancer. Prostate 70, 443–455 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  123. Hart, K. M., Byrne, K. T., Molloy, M. J., Usherwood, E. M. & Berwin, B. IL-10 immunomodulation of myeloid cells regulates a murine model of ovarian cancer. Front. Immunol. 2, 29 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  124. Sato, Y. et al. Characterization of the myeloid-derived suppressor cell subset regulated by NK cells in malignant lymphoma. Oncoimmunology 4, e995541 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  125. Hu, C.-E., Gan, J., Zhang, R.-D., Cheng, Y.-R. & Huang, G.-J. Up-regulated myeloid-derived suppressor cell contributes to hepatocellular carcinoma development by impairing dendritic cell function. Scand. J. Gastroenterol. 46, 156–164 (2011).

    Article  CAS  PubMed  Google Scholar 

  126. Sinha, P., Clements, V. K., Bunt, S. K., Albelda, S. M. & Ostrand-Rosenberg, S. Cross-talk between myeloid-derived suppressor cells and macrophages subverts tumor immunity toward a type 2 response1. J. Immunol. 179, 977–983 (2007).

    Article  CAS  PubMed  Google Scholar 

  127. Steinbrink, K., Graulich, E., Kubsch, S., Knop, J. & Enk, A. H. CD4+ and CD8+ anergic T cells induced by interleukin-10–treated human dendritic cells display antigen-specific suppressor activity. Blood 99, 2468–2476 (2002).

    Article  CAS  PubMed  Google Scholar 

  128. Steinbrink, K., Wölfl, M., Jonuleit, H., Knop, J. & Enk, A. H. Induction of tolerance by IL-10-treated dendritic cells. J. Immunol. 159, 4772–4780 (1997).

    Article  CAS  PubMed  Google Scholar 

  129. Serafini, P., Borrello, I. & Bronte, V. Myeloid suppressor cells in cancer: recruitment, phenotype, properties, and mechanisms of immune suppression. Semin. Cancer Biol. 16, 53–65 (2006).

    Article  CAS  PubMed  Google Scholar 

  130. Jianyi, D. et al. Myeloid-derived suppressor cells cross-talk with B10 cells by BAFF/BAFF-R pathway to promote immunosuppression in cervical cancer. Cancer Immunol. Immunother. 72, 73–85 (2023).

    Article  PubMed  Google Scholar 

  131. Filipazzi, P. et al. Identification of a new subset of myeloid suppressor cells in peripheral blood of melanoma patients with modulation by a granulocyte-macrophage colony-stimulation factor-based antitumor vaccine. J. Clin. Oncol. 25, 2546–2553 (2007).

    Article  CAS  PubMed  Google Scholar 

  132. Thomas, D. A. & Massagué, J. TGF-β directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. Cancer Cell 8, 369–380 (2005).

    Article  CAS  PubMed  Google Scholar 

  133. Mariathasan, S. et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554, 544–548 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Kobie, J. J. et al. Transforming growth factor β inhibits the antigen-presenting functions and antitumor activity of dendritic cell vaccines1. Cancer Res. 63, 1860–1864 (2003).

    CAS  PubMed  Google Scholar 

  135. 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-β11. J. Immunol. 182, 240–249 (2009).

    Article  CAS  PubMed  Google Scholar 

  136. Mao, Y. et al. Inhibition of tumor-derived prostaglandin-e2 blocks the induction of myeloid-derived suppressor cells and recovers natural killer cell activity. Clin. Cancer Res. 20, 4096–4106 (2014).

    Article  CAS  PubMed  Google Scholar 

  137. Burke, M., Choksawangkarn, W., Edwards, N., Ostrand-Rosenberg, S. & Fenselau, C. Exosomes from myeloid-derived suppressor cells carry biologically active proteins. J. Proteome Res. 13, 836–843 (2014).

    Article  CAS  PubMed  Google Scholar 

  138. Tumino, N. et al. Polymorphonuclear myeloid-derived suppressor cells are abundant in peripheral blood of cancer patients and suppress natural killer cell anti-tumor activity. Front. Immunol. 12, 803014 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  139. Gabrilovich, D. I. Myeloid-derived suppressor cells. Cancer Immunol. Res. 5, 3–8 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Yang, L. et al. Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell 6, 409–421 (2004).

    Article  CAS  PubMed  Google Scholar 

  141. Du, R. et al. HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell 13, 206–220 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Ahn, G. O. & Brown, J. M. Matrix metalloproteinase-9 is required for tumor vasculogenesis but not for angiogenesis: role of bone marrow-derived myelomonocytic cells. Cancer Cell 13, 193–205 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Shojaei, F. et al. Bv8 regulates myeloid-cell-dependent tumour angiogenesis. Nature 450, 825–831 (2007).

    Article  CAS  PubMed  Google Scholar 

  144. Qu, X., Zhuang, G., Yu, L., Meng, G. & Ferrara, N. Induction of Bv8 expression by granulocyte colony-stimulating factor in CD11b+Gr1+ cells: key role of Stat3 signaling. J. Biol. Chem. 287, 19574–19584 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Kujawski, M. et al. Stat3 mediates myeloid cell–dependent tumor angiogenesis in mice. J. Clin. Invest. 118, 3367–3377 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Bauer, R. et al. Blockade of myeloid-derived suppressor cell expansion with all-trans retinoic acid increases the efficacy of antiangiogenic therapy. Cancer Res. 78, 3220–3232 (2018).

    Article  CAS  PubMed  Google Scholar 

  147. Boelte, K. C. et al. Rgs2 mediates pro-angiogenic function of myeloid derived suppressor cells in the tumor microenvironment via upregulation of MCP-1. PLoS ONE 6, e18534 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Li, X. et al. Myeloid-derived suppressor cells promote epithelial ovarian cancer cell stemness by inducing the CSF2/p-STAT3 signalling pathway. FEBS J. 287, 5218–5235 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Cui, T. X. et al. Myeloid-derived suppressor cells enhance stemness of cancer cells by inducing microRNA101 and suppressing the corepressor CtBP2. Immunity 39, 611–621 (2013).

    Article  CAS  PubMed  Google Scholar 

  150. Luo, A. et al. Myeloid-derived suppressor cells recruited by chemokine (C-C motif) ligand 3 promote the progression of breast cancer via phosphoinositide 3-kinase-protein kinase B-mammalian target of rapamycin signaling. J. Breast Cancer 23, 141–161 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  151. Ai, L. et al. Myeloid-derived suppressor cells endow stem-like qualities to multiple myeloma cells by inducing piRNA-823 expression and DNMT3B activation. Mol. Cancer 18, 88 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  152. Sangaletti, S. et al. SPARC is a new myeloid-derived suppressor cell marker licensing suppressive activities. Front. Immunol. 10, 1369 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Panni, R. Z. et al. Tumor-induced STAT3 activation in monocytic myeloid-derived suppressor cells enhances stemness and mesenchymal properties in human pancreatic cancer. Cancer Immunol. Immunother. 63, 513–528 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Peng, D. et al. Myeloid-derived suppressor cells endow stem-like qualities to breast cancer cells through IL6/STAT3 and NO/NOTCH cross-talk signaling. Cancer Res. 76, 3156–3165 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Oh, K. et al. 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. 15, R79 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  156. Toh, B. et al. Mesenchymal transition and dissemination of cancer cells is driven by myeloid-derived suppressor cells infiltrating the primary tumor. PLoS Biol. 9, e1001162 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Ouzounova, M. et al. Monocytic and granulocytic myeloid derived suppressor cells differentially regulate spatiotemporal tumour plasticity during metastatic cascade. Nat. Commun. 8, 14979 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Lin, Y. et al. CAFs shape myeloid-derived suppressor cells to promote stemness of intrahepatic cholangiocarcinoma through 5-lipoxygenase. Hepatology 75, 28–42 (2022).

    Article  CAS  PubMed  Google Scholar 

  159. Kuroda, H. et al. Prostaglandin E2 produced by myeloid-derived suppressive cells induces cancer stem cells in uterine cervical cancer. Oncotarget 9, 36317–36330 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  160. Komura, N. et al. The role of myeloid-derived suppressor cells in increasing cancer stem-like cells and promoting PD-L1 expression in epithelial ovarian cancer. Cancer Immunol. Immunother. 69, 2477–2499 (2020).

    Article  CAS  PubMed  Google Scholar 

  161. Douglass, S. M. et al. Myeloid-derived suppressor cells are a major source of Wnt5A in the melanoma microenvironment and depend on Wnt5A for full suppressive activity. Cancer Res. 81, 658–670 (2021).

    Article  CAS  PubMed  Google Scholar 

  162. Zhang, R. et al. PMN-MDSCs modulated by CCL20 from cancer cells promoted breast cancer cell stemness through CXCL2–CXCR2 pathway. Signal. Transduct. Target. Ther. 8, 97 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Wang, Y. et al. Granulocytic myeloid-derived suppressor cells promote the stemness of colorectal cancer cells through exosomal S100A9. Adv. Sci. 6, 1901278 (2019).

    Article  CAS  Google Scholar 

  164. Yang, L. et al. Abrogation of TGFβ signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis. Cancer Cell 13, 23–35 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Pickup, M. W. et al. Stromally derived lysyl oxidase promotes metastasis of transforming growth factor-β-deficient mouse mammary carcinomas. Cancer Res. 73, 5336–5346 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Kowanetz, M. et al. Granulocyte-colony stimulating factor promotes lung metastasis through mobilization of Ly6G+Ly6C+ granulocytes. Proc. Natl Acad. Sci. USA 107, 21248–21255 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Hsu, Y.-L. et al. CXCL17-derived CD11b+Gr-1+ myeloid-derived suppressor cells contribute to lung metastasis of breast cancer through platelet-derived growth factor-BB. Breast Cancer Res. 21, 23 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  168. Spiegel, A. et al. Neutrophils suppress intraluminal NK cell-mediated tumor cell clearance and enhance extravasation of disseminated carcinoma cells. Cancer Discov. 6, 630–649 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Teijeira, Á. et al. CXCR1 and CXCR2 chemokine receptor agonists produced by tumors induce neutrophil extracellular traps that interfere with immune cytotoxicity. Immunity 52, 856–871.e8 (2020).

    Article  CAS  PubMed  Google Scholar 

  170. Albrengues, J. et al. Neutrophil extracellular traps produced during inflammation awaken dormant cancer cells in mice. Science 361, eaao4227 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  171. Sprouse, M. L. et al. PMN-MDSCs enhance CTC metastatic properties through reciprocal interactions via ROS/Notch/Nodal signaling. Int. J. Mol. Sci. 20, 1916 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Cao, Y. et al. BMP4 inhibits breast cancer metastasis by blocking myeloid-derived suppressor cell activity. Cancer Res. 74, 5091–5102 (2014).

    Article  CAS  PubMed  Google Scholar 

  173. Sceneay, J., Parker, B. S., Smyth, M. J. & Möller, A. Hypoxia-driven immunosuppression contributes to the pre-metastatic niche. Oncoimmunology 2, e22355 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  174. Wang, D., Sun, H., Wei, J., Cen, B. & DuBois, R. N. CXCL1 Is critical for premetastatic niche formation and metastasis in colorectal cancer. Cancer Res. 77, 3655–3665 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Wang, Y., Ding, Y., Guo, N. & Wang, S. MDSCs: key criminals of tumor pre-metastatic niche formation. Front. Immunol. 10, 172 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Yan, H. H. et al. Gr-1+CD11b+ myeloid cells tip the balance of immune protection to tumor promotion in the premetastatic lung. Cancer Res. 70, 6139–6149 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Kaplan, R. N. et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438, 820–827 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Shi, H. et al. Recruited monocytic myeloid-derived suppressor cells promote the arrest of tumor cells in the premetastatic niche through an IL-1β-mediated increase in E-selectin expression. Int. J. Cancer 140, 1370–1383 (2017).

    Article  CAS  PubMed  Google Scholar 

  179. Hiratsuka, S. et al. The S100A8–serum amyloid A3–TLR4 paracrine cascade establishes a pre-metastatic phase. Nat. Cell Biol. 10, 1349–1355 (2008).

    Article  CAS  PubMed  Google Scholar 

  180. Lim, S. Y. et al. Cd11b+ myeloid cells support hepatic metastasis through down-regulation of angiopoietin-like 7 in cancer cells. Hepatology 62, 521–533 (2015).

    Article  CAS  PubMed  Google Scholar 

  181. Gao, D. et al. Myeloid progenitor cells in the premetastatic lung promote metastases by inducing mesenchymal to epithelial transition. Cancer Res. 72, 1384–1394 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Catena, R. et al. Bone marrow-derived Gr1+ cells can generate a metastasis-resistant microenvironment via induced secretion of thrombospondin-1. Cancer Discov. 3, 578–589 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Shi, H., Li, K., Ni, Y., Liang, X. & Zhao, X. Myeloid-derived suppressor cells: implications in the resistance of malignant tumors to T cell-based immunotherapy. Front. Cell Dev. Biol. 9, 707198 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  184. Sánchez-León, M. L. et al. The effects of dendritic cell-based vaccines in the tumor microenvironment: impact on myeloid-derived suppressor cells. Front. Immunol. 13, 1050484 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  185. Li, X. et al. Targeting myeloid-derived suppressor cells to enhance the antitumor efficacy of immune checkpoint blockade therapy. Front. Immunol. 12, 754196 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Schoenfeld, A. J. & Hellmann, M. D. Acquired resistance to immune checkpoint inhibitors. Cancer Cell 37, 443–455 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Petrova, V. et al. Immunosuppressive capacity of circulating MDSC predicts response to immune checkpoint inhibitors in melanoma patients. Front. Immunol. 14, 1065767 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Limagne, E. et al. Tim-3/galectin-9 pathway and mMDSC control primary and secondary resistances to PD-1 blockade in lung cancer patients. Oncoimmunology 8, e1564505 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  189. Theivanthiran, B. et al. A tumor-intrinsic PD-L1/NLRP3 inflammasome signaling pathway drives resistance to anti-PD-1 immunotherapy. J. Clin. Invest. 130, 2570–2586 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Quail, D. F. et al. The tumor microenvironment underlies acquired resistance to CSF-1R inhibition in gliomas. Science 352, aad3018 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  191. Weber, R. et al. Myeloid-derived suppressor cells hinder the anti-cancer activity of immune checkpoint inhibitors. Front. Immunol. 9, 1310 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  192. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Zhang, Z. et al. A drug screening to identify novel combinatorial strategies for boosting cancer immunotherapy efficacy. J. Transl. Med. 21, 23 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Bendell, J. et al. First-in-human study of oleclumab, a potent, selective anti-CD73 monoclonal antibody, alone or in combination with durvalumab in patients with advanced solid tumors. Cancer Immunol. Immunother. 72, 2443–2458 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Kondo, S. et al. Safety, tolerability, pharmacokinetics, and antitumour activity of oleclumab in Japanese patients with advanced solid malignancies: a phase I, open-label study. Int. J. Clin. Oncol. 27, 1795–1804 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Zhang, H. et al. Glycoengineered anti-CD39 promotes anticancer responses by depleting suppressive cells and inhibiting angiogenesis in tumor models. J. Clin. Invest. 132, e157431 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Jahani, V., Yazdani, M., Badiee, A., Jaafari, M. R. & Arabi, L. Liposomal celecoxib combined with dendritic cell therapy enhances antitumor efficacy in melanoma. J. Control. Rel. 354, 453–464 (2023).

    Article  CAS  Google Scholar 

  198. Gandhi, S. et al. 547 Safety and efficacy of de-escalated neoadjuvant chemoimmunotherapy of triple negative breast cancer (TNBC) using chemokine-modulating regimen (rintatolimod, IFN-α2b, celecoxib). J. Immunother. Cancer 10, A572 (2022).

    Google Scholar 

  199. Kjeldsen, J. W. et al. A phase 1/2 trial of an immune-modulatory vaccine against IDO/PD-L1 in combination with nivolumab in metastatic melanoma. Nat. Med. 27, 2212–2223 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. 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).

    Article  CAS  PubMed  Google Scholar 

  201. Fleet, J. C., Burcham, G. N., Calvert, R. D., Elzey, B. D. & Ratliff, T. L. 1α, 25 Dihydroxyvitamin D (1,25(OH)2D) inhibits the T cell suppressive function of myeloid derived suppressor cells (MDSC). J. Steroid Biochem. Mol. Biol. 198, 105557 (2020).

    Article  CAS  PubMed  Google Scholar 

  202. Nefedova, Y. et al. Mechanism of all-trans retinoic acid effect on tumor-associated myeloid-derived suppressor cells. Cancer Res. 67, 11021–11028 (2007).

    Article  CAS  PubMed  Google Scholar 

  203. Li, L. et al. Metformin-induced reduction of CD39 and CD73 blocks myeloid-derived suppressor cell activity in patients with ovarian cancer. Cancer Res. 78, 1779–1791 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Qin, G. et al. Metformin blocks myeloid-derived suppressor cell accumulation through AMPK-DACH1-CXCL1 axis. Oncoimmunology 7, e1442167 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  205. Dominguez, G. A. et al. Selective targeting of myeloid-derived suppressor cells in cancer patients using DS-8273a, an agonistic TRAIL-R2 antibody. Clin. Cancer Res. 23, 2942–2950 (2017).

    Article  CAS  PubMed  Google Scholar 

  206. Tavazoie, M. F. et al. LXR/ApoE activation restricts innate immune suppression in cancer. Cell 172, 825–840.e18 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Cheng, P. et al. Immunodepletion of MDSC by AMV564, a novel bivalent, bispecific CD33/CD3 T cell engager, ex vivo in MDS and melanoma. Mol. Ther. 30, 2315–2326 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Fultang, L. et al. MDSC targeting with Gemtuzumab ozogamicin restores T cell immunity and immunotherapy against cancers. eBioMedicine 47, 235–246 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  209. Garg, A. D. et al. Trial watch: immunogenic cell death induction by anticancer chemotherapeutics. Oncoimmunology 6, e1386829 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  210. Welters, M. J. et al. Vaccination during myeloid cell depletion by cancer chemotherapy fosters robust T cell responses. Sci. Transl. Med. 8, 334ra352 (2016).

    Article  Google Scholar 

  211. Dijkgraaf, E. M. et al. A phase 1/2 study combining gemcitabine, Pegintron and p53 SLP vaccine in patients with platinum-resistant ovarian cancer. Oncotarget 6, 32228–32243 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  212. Vincent, J. et al. 5-fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res. 70, 3052–3061 (2010).

    Article  CAS  PubMed  Google Scholar 

  213. Sevko, A. et al. Antitumor effect of paclitaxel is mediated by inhibition of myeloid-derived suppressor cells and chronic inflammation in the spontaneous melanoma model. J. Immunol. 190, 2464–2471 (2013).

    Article  CAS  PubMed  Google Scholar 

  214. Gebhardt, C. et al. Potential therapeutic effect of low-dose paclitaxel in melanoma patients resistant to immune checkpoint blockade: a pilot study. Cell. Immunol. 360, 104274 (2021).

    Article  CAS  PubMed  Google Scholar 

  215. Huijts, C. M. et al. The effect of everolimus and low-dose cyclophosphamide on immune cell subsets in patients with metastatic renal cell carcinoma: results from a phase I clinical trial. Cancer Immunol. Immunother. 68, 503–515 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Perrot, I. et al. Blocking antibodies targeting the CD39/CD73 immunosuppressive pathway unleash immune responses in combination cancer therapies. Cell Rep. 27, 2411–2425.e9 (2019).

    Article  CAS  PubMed  Google Scholar 

  218. Diaz-Montero, C. M. et al. Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin–cyclophosphamide chemotherapy. Cancer Immunol. Immunother. 58, 49–59 (2009).

    Article  CAS  PubMed  Google Scholar 

  219. Deng, Z. et al. Exosomes miR-126a released from MDSC induced by DOX treatment promotes lung metastasis. Oncogene 36, 639–651 (2017).

    Article  CAS  PubMed  Google Scholar 

  220. Ko, J. S. et al. Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients. Clin. Cancer Res. 15, 2148–2157 (2009).

    Article  CAS  PubMed  Google Scholar 

  221. Zahoor, H. et al. Phase II trial of continuous treatment with sunitinib in patients with high-risk (BCG-refractory) non-muscle invasive bladder cancer. Invest. New Drugs 37, 1231–1238 (2019).

    Article  CAS  PubMed  Google Scholar 

  222. Overman, M. et al. Randomized phase II study of the Bruton tyrosine kinase inhibitor acalabrutinib, alone or with pembrolizumab in patients with advanced pancreatic cancer. J. Immunother. Cancer 8, e000587 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  223. Refaat, Y., Rahman, Y. A., Mohammed Saleh, M. F., Sayed, D. M. & Elzohri, M. H. Tyrosine kinase inhibitors reduce myeloid-derived suppressor cells in patients with chronic myeloid leukemia with better outcome. Egypt. J. Haematol. 47, 272–280 (2022).

    Article  Google Scholar 

  224. Schilling, B. et al. Vemurafenib reverses immunosuppression by myeloid derived suppressor cells. Int. J. Cancer 133, 1653–1663 (2013).

    Article  CAS  PubMed  Google Scholar 

  225. Ghonim, M. A. et al. Targeting PARP-1 with metronomic therapy modulates MDSC suppressive function and enhances anti-PD-1 immunotherapy in colon cancer. J. Immunother. Cancer 9, e001643 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  226. Ibba, S. V., Luu, H. H. & Boulares, A. H. Differential effects of poly(ADP ribose) polymerase inhibitor-based metronomic therapy on programmed death-ligand 1 and matrix-associated factors in human myeloid cells. Am. J. Transl. Res. 14, 9025–9030 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  227. Tomita, Y. et al. The interplay of epigenetic therapy and immunity in locally recurrent or metastatic estrogen receptor-positive breast cancer: correlative analysis of ENCORE 301, a randomized, placebo-controlled phase II trial of exemestane with or without entinostat. Oncoimmunology 5, e1219008 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  228. Lu, Z. et al. Epigenetic therapy inhibits metastases by disrupting premetastatic niches. Nature 579, 284–290 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Wang, Q. et al. Reversing myeloid-derived suppressor cells mediated immunosuppression via p38α inhibition enhances immunotherapy efficacy in triple negative breast cancer. Preprint at bioRxiv https://doi.org/10.1101/2023.03.31.535102 (2023).

  230. Cao, M. et al. Kinase inhibitor Sorafenib modulates immunosuppressive cell populations in a murine liver cancer model. Lab. Invest. 91, 598–608 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Apetoh, L. et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat. Med. 13, 1050–1059 (2007).

    Article  CAS  PubMed  Google Scholar 

  232. Mao, L. et al. Immunogenic hypofractionated radiotherapy sensitising head and neck squamous cell carcinoma to anti-PD-L1 therapy in MDSC-dependent manner. Br. J. Cancer 128, 11 (2023).

    Article  Google Scholar 

  233. Iliadi, C. et al. The current understanding of the immune landscape relative to radiotherapy across tumor types. Front. Immunol. 14, 1148692 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Ostrand-Rosenberg, S., Horn, L. A. & Ciavattone, N. G. Radiotherapy both promotes and inhibits myeloid-derived suppressor cell function: novel strategies for preventing the tumor-protective effects of radiotherapy. Front. Oncol. 9, 215 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  235. Svoronos, N. et al. Tumor cell-independent estrogen signaling drives disease progression through mobilization of myeloid-derived suppressor cells. Cancer Discov. 7, 72–85 (2017).

    Article  CAS  PubMed  Google Scholar 

  236. Bergenfelz, C. et al. Systemic monocytic-MDSCs are generated from monocytes and correlate with disease progression in breast cancer patients. PLoS ONE 10, e0127028 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  237. Larsson, A.-M., Roxå, A., Leandersson, K. & Bergenfelz, C. Impact of systemic therapy on circulating leukocyte populations in patients with metastatic breast cancer. Sci. Rep. 9, 13451 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  238. Márquez-Garbán, D. C. et al. Antiestrogens in combination with immune checkpoint inhibitors in breast cancer immunotherapy. J. Steroid Biochem. Mol. Biol. 193, 105415 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  239. Milette, S. et al. Sexual dimorphism and the role of estrogen in the immune microenvironment of liver metastases. Nat. Commun. 10, 5745 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Qin, C., Wang, J., Du, Y. & Xu, T. Immunosuppressive environment in response to androgen deprivation treatment in prostate cancer. Front. Endocrinol. 13, 1055826 (2022).

    Article  Google Scholar 

  241. Xu, P. et al. Androgen receptor blockade resistance with enzalutamide in prostate cancer results in immunosuppressive alterations in the tumor immune microenvironment. J. Immunother. Cancer 11, e006581 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  242. Wang, D. et al. IL-1β is an androgen-responsive target in macrophages for immunotherapy of prostate cancer. Adv. Sci. 10, 2206889 (2023).

    Article  CAS  Google Scholar 

  243. Lopez-Bujanda, Z. A. et al. Castration-mediated IL-8 promotes myeloid infiltration and prostate cancer progression. Nat. Cancer 2, 803–818 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Consiglio, C. R., Udartseva, O., Ramsey, K. D., Bush, C. & Gollnick, S. O. Enzalutamide, an androgen receptor antagonist, enhances myeloid cell-mediated immune suppression and tumor progression. Cancer Immunol. Res. 8, 1215–1227 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. Calcinotto, A. et al. IL-23 secreted by myeloid cells drives castration-resistant prostate cancer. Nature 559, 363–369 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. Pienta, K. J. et al. Phase 2 study of carlumab (CNTO 888), a human monoclonal antibody against CC-chemokine ligand 2 (CCL2), in metastatic castration-resistant prostate cancer. Invest. New Drugs 31, 760–768 (2013).

    Article  CAS  PubMed  Google Scholar 

  247. Brana, I. et al. Carlumab, an anti-C-C chemokine ligand 2 monoclonal antibody, in combination with four chemotherapy regimens for the treatment of patients with solid tumors: an open-label, multicenter phase 1b study. Target. Oncol. 10, 111–123 (2015).

    Article  PubMed  Google Scholar 

  248. Nywening, T. M. et al. Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial. Lancet Oncol. 17, 651–662 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  249. Halama, N. et al. Tumoral immune cell exploitation in colorectal cancer metastases can be targeted effectively by anti-CCR5 therapy in cancer patients. Cancer Cell 29, 587–601 (2016).

    Article  CAS  PubMed  Google Scholar 

  250. Haag, G. M. et al. Pembrolizumab and maraviroc in refractory mismatch repair proficient/microsatellite-stable metastatic colorectal cancer — the PICCASSO phase I trial. Eur. J. Cancer 167, 112–122 (2022).

    Article  CAS  PubMed  Google Scholar 

  251. Johnson, M. et al. ARRY-382 in combination with pembrolizumab in patients with advanced solid tumors: results from a phase 1b/2 study. Clin. Cancer Res. 28, 2517–2526 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  252. Machiels, J.-P. et al. Phase Ib study of anti-CSF-1R antibody emactuzumab in combination with CD40 agonist selicrelumab in advanced solid tumor patients. J. Immunother. Cancer 8, e001153 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  253. Gomez-Roca, C. et al. Anti-CSF-1R emactuzumab in combination with anti-PD-L1 atezolizumab in advanced solid tumor patients naïve or experienced for immune checkpoint blockade. J. Immunother. Cancer 10, e004076 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  254. Autio, K. A. et al. Immunomodulatory activity of a colony-stimulating factor-1 receptor inhibitor in patients with advanced refractory breast or prostate cancer: a phase I study. Clin. Cancer Res. 26, 5609–5620 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. Dowlati, A. et al. LY3022855, an anti–colony stimulating factor-1 receptor (CSF-1R) monoclonal antibody, in patients with advanced solid tumors refractory to standard therapy: phase 1 dose-escalation trial. Invest. New Drugs 39, 1057–1071 (2021).

    Article  CAS  PubMed  Google Scholar 

  256. Falchook, G. S. et al. A phase 1a/1b trial of CSF-1R inhibitor LY3022855 in combination with durvalumab or tremelimumab in patients with advanced solid tumors. Invest. New Drugs 39, 1284–1297 (2021).

    Article  CAS  PubMed  Google Scholar 

  257. Schott, A. F. et al. Phase Ib pilot study to evaluate reparixin in combination with weekly paclitaxel in patients with HER-2-negative metastatic breast cancer. Clin. Cancer Res. 23, 5358–5365 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  258. Goldstein, L. J. et al. A randomized, placebo-controlled phase 2 study of paclitaxel in combination with reparixin compared to paclitaxel alone as front-line therapy for metastatic triple-negative breast cancer (fRida). Breast Cancer Res. Treat. 190, 265–275 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  259. Bockorny, B. et al. BL-8040, a CXCR4 antagonist, in combination with pembrolizumab and chemotherapy for pancreatic cancer: the COMBAT trial. Nat. Med. 26, 878–885 (2020).

    Article  CAS  PubMed  Google Scholar 

  260. Biasci, D. et al. CXCR4 inhibition in human pancreatic and colorectal cancers induces an integrated immune response. Proc. Natl Acad. Sci. USA 117, 28960–28970 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  261. Proia, T. A. et al. STAT3 antisense oligonucleotide remodels the suppressive tumor microenvironment to enhance immune activation in combination with anti–PD-L1. Clin. Cancer Res. 26, 6335–6349 (2020).

    Article  CAS  PubMed  Google Scholar 

  262. Nishina, T. et al. Safety, tolerability, pharmacokinetics and preliminary antitumour activity of an antisense oligonucleotide targeting STAT3 (danvatirsen) as monotherapy and in combination with durvalumab in Japanese patients with advanced solid malignancies: a phase 1 study. BMJ Open 12, e055718 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  263. Miller, J. S. et al. 965MO GTB-3550 tri-specific killer engager safely activates and delivers IL-15 to NK cells, but not T-cells, in immune suppressed patients with advanced myeloid malignancies, a novel paradigm exportable to solid tumors expressing Her2 or B7H3. Ann. Oncol. 32, S834 (2021).

    Article  Google Scholar 

  264. Lorentzen, C. L. et al. Arginase-1 targeting peptide vaccine in patients with metastatic solid tumors — a phase I trial. Front. Immunol. 13, 1023023 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  265. Hashimoto, A. et al. Upregulation of C/EBPα inhibits suppressive activity of myeloid cells and potentiates antitumor response in mice and patients with cancer. Clin. Cancer Res. 27, 5961–5978 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  266. Meyerhardt, J. A. et al. Effect of celecoxib vs placebo added to standard adjuvant therapy on disease-free survival among patients with stage III colon cancer: the CALGB/SWOG 80702 (Alliance) randomized clinical trial. JAMA 325, 1277–1286 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  267. James, N. D. et al. Celecoxib plus hormone therapy versus hormone therapy alone for hormone-sensitive prostate cancer: first results from the STAMPEDE multiarm, multistage, randomised controlled trial. Lancet Oncol. 13, 549–558 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  268. Mason, M. D. et al. Adding celecoxib with or without zoledronic acid for hormone-naïve prostate cancer: long-term survival results from an adaptive, multiarm, multistage, platform, randomized controlled trial. J. Clin. Oncol. 35, 1530–1541 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  269. Iversen, T. Z. et al. Long-lasting disease stabilization in the absence of toxicity in metastatic lung cancer patients vaccinated with an epitope derived from indoleamine 2,3 dioxygenase. Clin. Cancer Res. 20, 221–232 (2014).

    Article  CAS  PubMed  Google Scholar 

  270. Bjoern, J., Iversen, T. Z., Nitschke, N. J., Andersen, M. H. & Svane, I. M. Safety, immune and clinical responses in metastatic melanoma patients vaccinated with a long peptide derived from indoleamine 2,3-dioxygenase in combination with ipilimumab. Cytotherapy 18, 1043–1055 (2016).

    Article  CAS  PubMed  Google Scholar 

  271. Komrokji, R. S. et al. A phase II study to determine the safety and efficacy of the oral inhibitor of indoleamine 2,3-dioxygenase (IDO) enzyme INCB024360 in patients with myelodysplastic syndromes. Clin. Lymphoma Myeloma Leuk. 19, 157–161 (2019).

    Article  PubMed  Google Scholar 

  272. Powderly, J. D. et al. Epacadostat plus pembrolizumab and chemotherapy for advanced solid tumors: results from the phase I/II ECHO-207/KEYNOTE-723 study. Oncologist 27, 905–e848 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  273. Johnson, T. S. et al. Indoximod-based chemo-immunotherapy for pediatric brain tumors: a first-in-children phase 1 trial.Neuro-Oncology https://doi.org/10.1093/neuonc/noad174 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  274. Nayak-Kapoor, A. et al. Phase Ia study of the indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor navoximod (GDC-0919) in patients with recurrent advanced solid tumors. J. Immunother. Cancer 6, 61 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  275. Patel, S. P. et al. A phase 1b/2 study of omaveloxolone in combination with checkpoint inhibitors in patients with unresectable or metastatic melanoma. Ann. Oncol. 28, xi30 (2017).

    Article  Google Scholar 

  276. Califano, J. A. et al. Tadalafil augments tumor specific immunity in patients with head and neck squamous cell carcinoma. Clin. Cancer Res. 21, 30–38 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  277. Weed, D. T. et al. Tadalafil reduces myeloid-derived suppressor cells and regulatory T cells and promotes tumor immunity in patients with head and neck squamous cell carcinoma. Clin. Cancer Res. 21, 39–48 (2015).

    Article  CAS  PubMed  Google Scholar 

  278. Weed, D. T. et al. The reversal of immune exclusion mediated by tadalafil and an anti-tumor vaccine also induces PDL1 upregulation in recurrent head and neck squamous cell carcinoma: interim analysis of a phase I clinical trial. Front. Immunol. 10, 1206 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  279. Iclozan, C., Antonia, S., Chiappori, A., Chen, D.-T. & Gabrilovich, D. Therapeutic regulation of myeloid-derived suppressor cells and immune response to cancer vaccine in patients with extensive stage small cell lung cancer. Cancer Immunol. Immunother. 62, 909–918 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  280. Tobin, R. P. et al. Targeting myeloid-derived suppressor cells using all-trans retinoic acid in melanoma patients treated with Ipilimumab. Int. Immunopharmacol. 63, 282–291 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  281. Tobin, R. P. et al. Targeting MDSC differentiation using ATRA: a phase I/II clinical trial combining pembrolizumab and all-trans retinoic acid for metastatic melanoma. Clin. Cancer Res. 29, 1209–1219 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  282. Shayan, G. et al. Phase Ib study of immune biomarker modulation with neoadjuvant cetuximab and TLR8 stimulation in head and neck cancer to overcome suppressive myeloid signals. Clin. Cancer Res. 24, 62–72 (2018).

    Article  CAS  PubMed  Google Scholar 

  283. Yamauchi, Y. et al. Circulating and tumor myeloid-derived suppressor cells in resectable non-small cell lung cancer. Am. J. Respir. Crit. Care Med. 198, 777–787 (2018).

    Article  PubMed  Google Scholar 

  284. Kim, H. R. et al. The ratio of peripheral regulatory T cells to lox-1+ polymorphonuclear myeloid-derived suppressor cells predicts the early response to anti-PD-1 therapy in patients with non-small cell lung cancer. Am. J. Respir. Crit. Care Med. 199, 243–246 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  285. Si, Y. et al. Multidimensional imaging provides evidence for down-regulation of T cell effector function by MDSC in human cancer tissue. Sci. Immunol. 4, eaaw9159 (2019).

    Article  CAS  PubMed  Google Scholar 

  286. Engblom, C. et al. Osteoblasts remotely supply lung tumors with cancer-promoting SiglecFhigh neutrophils. Science 358, eaal5081 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  287. Zilionis, R. et al. Single-cell transcriptomics of human and mouse lung cancers reveals conserved myeloid populations across individuals and species. Immunity 50, 1317–1334.e10 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany

    Samantha A. Lasser, Feyza G. Ozbay Kurt, Ihor Arkhypov, Jochen Utikal & Viktor Umansky

  2. Skin Cancer Unit, German Cancer Research Center (Deutsches Krebsforschungszentrum (DKFZ)), Heidelberg, Germany

    Samantha A. Lasser, Feyza G. Ozbay Kurt, Ihor Arkhypov, Jochen Utikal & Viktor Umansky

  3. DKFZ-Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, Germany

    Samantha A. Lasser, Feyza G. Ozbay Kurt, Ihor Arkhypov, Jochen Utikal & Viktor Umansky

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S.A.L. and V.U. researched data for the article and wrote the manuscript. All authors contributed substantially to the discussion of content and reviewed and/or edited the manuscript before submission.

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Lasser, S.A., Ozbay Kurt, F.G., Arkhypov, I. et al. Myeloid-derived suppressor cells in cancer and cancer therapy. Nat Rev Clin Oncol 21, 147–164 (2024). https://doi.org/10.1038/s41571-023-00846-y

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