Cancer-cell-intrinsic mechanisms regulate MDSCs through cytokine networks

Immunotherapy has shifted the paradigm of cancer treatment. However, the majority of cancer patients display de novo or acquired resistance to immunotherapy. One of the main mechanisms of immunotherapy resistance is the immunosuppressive microenvironment dominated by the myeloid-derived suppressor cells (MDSCs). Emerging evidence demonstrates that genetic or epigenetic aberrations in cancer cells shape the accumulation and activation of MDSCs. Understanding this genotype-immunophenotype relationship is critical to the rational design of combination immunotherapy. Here, we review the mechanisms of how molecular changes in cancer cells induce recruitment and reprogram the function of tumor-infiltrating myeloid cells, particularly MDSCs. Tumor-infiltrating MDSCs elicit various pro-tumor functions to promote tumor cell fitness, immune evasion, angiogenesis, tissue remodeling, and metastasis. Through understanding the genotype-immunophenotype relationship between neoplastic cells and MDSCs, new approaches can be developed to tailor current immunotherapy strategies to improve cancer patient outcomes.