Cancer immunotherapy has been established as the fifth pillar of cancer therapy. However, many patients, such as prostate cancer patients, receive limited benefits from immunotherapy (Sharma and Allison, 2015; Topalian et al., 2012). Among the tumor-infiltrating immune cells in the tumor microenvironment (TME), myeloid-derived suppressor cells (MDSCs) are a major group of immunosuppressive cells (Gabrilovich et al., 2007). MDSCs are immature myeloid cells released from bone marrow as a consequence of aberrantly activated myelopoiesis and granulopoiesis. Among MDSCs, polymorphonuclear MDSCs (PMN-MDSCs) are defined as CD45+ CD11b+ Ly6G+ Ly6Cmed-low cells in tumor-bearing murine models and CD11b+CD33+CD15+(CD66b+) CD14− HLA-DR− cells in human cancer patients. These cells are also often referred to as granulocytic-MDSCs (G-MDSCs), N2 tumor-associated neutrophils (TANs), or immunosuppressive neutrophils. Monocytic-MDSCs (M-MDSCs) are defined as CD45+CD11b+Ly6G− Ly6Chigh population in mice and as CD11b+CD33+CD14+ HLA-DR−/lo CD15− cells in human patients (Bronte et al., 2016; Fang et al., 2017; Kumar et al., 2016; Masucci et al., 2019; Ohms et al., 2020; Youn et al., 2008). M-MDSCs can rapidly differentiate into tumor-associated macrophages (TAMs) in the TME. Although M-MDSCs and TAMs are separate populations, they share many similarities, primarily in recruitment and immunosuppressive mechanisms (Ugel et al., 2015).

Therapeutic targeting of MDSCs is a promising approach to enhancing cancer immunotherapy. However, because partially overlapping mechanisms operate to control the production and activity of MDSCs and physiological counterparts (neutrophils, monocytes), targeting cancer-cell-intrinsic mechanisms that specifically regulate MDSCs could provide more clinically feasible strategies to reduce cancer-promoting MDSCs. In this review, we will summarize recent findings of cancer-cell-intrinsic signaling mechanisms that regulate MDSCs in the TME.