Myeloid-derived suppressor cells in the tumor microenvironment: cellular crosstalk, immunosuppressive effects, and therapeutic targets.
Tumor microenvironment (TME)-induced immunosuppression is a major driver of cancer treatment failure and resistance to immunotherapy. Myeloid-derived suppressor cells (MDSCs) are not only pivotal suppressors of effector immune responses but also central organizers of tumor-supportive metabolic, stromal, and cellular crosstalk. This review systematically summarizes the origin and phenotypic characteristics of MDSCs and the mechanisms governing their recruitment, expansion, and activation within the TME. This review integrates current knowledge of MDSC biology through two complementary frameworks. One framework highlights the bidirectional interactions between MDSCs and immune, tumor, stromal, endothelial, and adipocyte compartments. The other classifies therapeutic approaches according to their mechanisms and translational relevance, including combinations with immunotherapy. We further evaluate clinical translation, including lessons from unsuccessful or inconclusive trials, biomarker gaps, and rational combination strategies. Together, current evidence indicates that MDSCs represent context-dependent therapeutic nodes, while functional reprogramming, spatially resolved profiling, and patient stratification may improve immunotherapy outcomes.