Myeloid-derived Suppressor Cells (MDSCs) in the Tumor Microenvironment and Their Targeting in Cancer Therapy

Overview

Journal Mol Cancer

Publisher Biomed Central

Date 2025 Jan 9

PMID 39780248

Authors

Shuyan He

Lu Zheng

Chunjian Qi

Affiliations

Soon will be listed here.

Abstract

The advent of immunotherapy represents a significant breakthrough in cancer treatment, with immune checkpoint inhibitors (ICIs) targeting PD-1 and CTLA-4 demonstrating remarkable therapeutic efficacy. However, patient responses to immunotherapy vary significantly, with immunosuppression within the tumor microenvironment (TME) being a critical factor influencing this variability. Immunosuppression plays a pivotal role in regulating cancer progression, metastasis, and reducing the success rates of immunotherapy. Myeloid-derived suppressor cells (MDSCs), due to their potent immunosuppressive capabilities, emerged as major negative regulators within the TME, facilitating tumor immune evasion by modulating various immune cells. In addition to their immunosuppressive functions, MDSCs also promote tumor growth and metastasis through non-immunological mechanisms, such as angiogenesis and the formation of pre-metastatic niches. Consequently, MDSCs in the TME are key regulators of cancer immune responses and potential therapeutic targets in cancer treatment. This review describes the origins and phenotypes of MDSCs, their biological roles in tumor progression, and regulatory mechanisms, with a focus on current therapeutic approaches targeting tumor-associated MDSCs. Furthermore, the synergistic effects of targeting MDSCs in combination with immunotherapy are explored, aiming to provide new insights and directions for cancer therapy.

References

Calcinotto A, Spataro C, Zagato E, Di Mitri D, Gil V, Crespo M . IL-23 secreted by myeloid cells drives castration-resistant prostate cancer. Nature. 2018; 559(7714):363-369. PMC: 6461206. DOI: 10.1038/s41586-018-0266-0. View

Ma W, Li Z, Wu Z, Liu F, Wang J, Shi Y . PI3K-CCL2-CCR2-MDSCs axis: A potential pathway for tumor Clostridia-promoted CD 8 T lymphocyte infiltration in bile tract cancers. Neoplasia. 2023; 43:100920. PMC: 10407443. DOI: 10.1016/j.neo.2023.100920. View

Veglia F, Tyurin V, Blasi M, De Leo A, Kossenkov A, Donthireddy L . Fatty acid transport protein 2 reprograms neutrophils in cancer. Nature. 2019; 569(7754):73-78. PMC: 6557120. DOI: 10.1038/s41586-019-1118-2. View

Pi R, Yang Y, Hu X, Li H, Shi H, Liu Y . Dual mTORC1/2 inhibitor AZD2014 diminishes myeloid-derived suppressor cells accumulation in ovarian cancer and delays tumor growth. Cancer Lett. 2021; 523:72-81. DOI: 10.1016/j.canlet.2021.09.017. View

Cui Y, Cai J, Wang W, Wang S . Regulatory Effects of Histone Deacetylase Inhibitors on Myeloid-Derived Suppressor Cells. Front Immunol. 2021; 12:690207. PMC: 8208029. DOI: 10.3389/fimmu.2021.690207. View

Li B, Luo Y, Zhou Y, Wu J, Fang Z, Li Y . Role of sanguinarine in regulating immunosuppression in a Lewis lung cancer mouse model. Int Immunopharmacol. 2022; 110:108964. DOI: 10.1016/j.intimp.2022.108964. View

Carlson E, Savardekar H, Hu X, Lapurga G, Johnson C, Sun S . Fluorescent Detection of Peroxynitrite Produced by Myeloid-Derived Suppressor Cells in Cancer and Inhibition by Dasatinib. ACS Pharmacol Transl Sci. 2023; 6(5):738-747. PMC: 10186365. DOI: 10.1021/acsptsci.3c00014. View

Porta C, Consonni F, Morlacchi S, Sangaletti S, Bleve A, Totaro M . Tumor-Derived Prostaglandin E2 Promotes p50 NF-κB-Dependent Differentiation of Monocytic MDSCs. Cancer Res. 2020; 80(13):2874-2888. DOI: 10.1158/0008-5472.CAN-19-2843. View

Sharma V, Sachdeva N, Gupta V, Nada R, Jacob J, Sahni D . CCR4 monocytic myeloid-derived suppressor cells are associated with the increased epithelial-mesenchymal transition in pancreatic adenocarcinoma patients. Immunobiology. 2022; 227(3):152210. DOI: 10.1016/j.imbio.2022.152210. View

10.

Tian X, Wang T, Shen H, Wang S . Tumor microenvironment, histone modifications, and myeloid-derived suppressor cells. Cytokine Growth Factor Rev. 2023; 74:108-121. DOI: 10.1016/j.cytogfr.2023.08.002. View

11.

Liu Y, Wong C, Ding Y, Gao M, Wen J, Lau H . Peptostreptococcus anaerobius mediates anti-PD1 therapy resistance and exacerbates colorectal cancer via myeloid-derived suppressor cells in mice. Nat Microbiol. 2024; 9(6):1467-1482. PMC: 11153135. DOI: 10.1038/s41564-024-01695-w. View

12.

Alshetaiwi H, Pervolarakis N, McIntyre L, Ma D, Nguyen Q, Rath J . Defining the emergence of myeloid-derived suppressor cells in breast cancer using single-cell transcriptomics. Sci Immunol. 2020; 5(44). PMC: 7219211. DOI: 10.1126/sciimmunol.aay6017. View

13.

Reilley M, McCoon P, Cook C, Lyne P, Kurzrock R, Kim Y . STAT3 antisense oligonucleotide AZD9150 in a subset of patients with heavily pretreated lymphoma: results of a phase 1b trial. J Immunother Cancer. 2018; 6(1):119. PMC: 6240242. DOI: 10.1186/s40425-018-0436-5. View

14.

Lazarova M, Steinle A . Impairment of NKG2D-Mediated Tumor Immunity by TGF-β. Front Immunol. 2019; 10:2689. PMC: 6873348. DOI: 10.3389/fimmu.2019.02689. View

15.

Walter S, Weinschenk T, Stenzl A, Zdrojowy R, Pluzanska A, Szczylik C . Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival. Nat Med. 2012; 18(8):1254-61. DOI: 10.1038/nm.2883. View

16.

Karpisheh V, Nikkhoo A, Hojjat-Farsangi M, Namdar A, Azizi G, Ghalamfarsa G . Prostaglandin E2 as a potent therapeutic target for treatment of colon cancer. Prostaglandins Other Lipid Mediat. 2019; 144:106338. DOI: 10.1016/j.prostaglandins.2019.106338. View

17.

Kodumudi K, Woan K, Gilvary D, Sahakian E, Wei S, Djeu J . A novel chemoimmunomodulating property of docetaxel: suppression of myeloid-derived suppressor cells in tumor bearers. Clin Cancer Res. 2010; 16(18):4583-94. PMC: 3874864. DOI: 10.1158/1078-0432.CCR-10-0733. View

18.

Le H, Wang Y, Zhou J, Li D, Gong Z, Zhu F . Git2 deficiency promotes MDSCs recruitment in intestine via NF-κB-CXCL1/CXCL12 pathway and ameliorates necrotizing enterocolitis. Mucosal Immunol. 2024; 17(5):1060-1071. DOI: 10.1016/j.mucimm.2024.07.006. View

19.

Masuda T, Noda M, Kogawa T, Kitagawa D, Hayashi N, Jomori T . Phase I dose-escalation trial to repurpose propagermanium, an oral CCL2 inhibitor, in patients with breast cancer. Cancer Sci. 2020; 111(3):924-931. PMC: 7060487. DOI: 10.1111/cas.14306. View

20.

Orillion A, Hashimoto A, Damayanti N, Shen L, Adelaiye-Ogala R, Arisa S . Entinostat Neutralizes Myeloid-Derived Suppressor Cells and Enhances the Antitumor Effect of PD-1 Inhibition in Murine Models of Lung and Renal Cell Carcinoma. Clin Cancer Res. 2017; 23(17):5187-5201. PMC: 5723438. DOI: 10.1158/1078-0432.CCR-17-0741. View