Targeting Myeloid-Derived Suppressor Cells in Sepsis: Pathophysiology, Duality, and Therapeutic Frontiers

Sepsis-induced immunosuppression, one of the factors contributing to mortality, is closely mediated by Myeloid-Derived Suppressor Cells (MDSCs). This review first outlines MDSC biology, describing their origin from pathological emergency myelopoiesis and classification into polymorphonuclear (PMN-MDSCs) and monocytic (M-MDSCs) subsets. We then discuss their dual role: an early, protective modulation of cytokine storm that later evolves into harmful immunosuppression associated with secondary infections and death. The underlying mechanisms involve L-arginine depletion (via ARG1/iNOS), oxidative stress (ROS), and induction of regulatory T cells (Tregs). Therapeutic strategies are summarized, including interventions targeting MDSC differentiation (e.g., ATRA), metabolism (e.g., FAO inhibitors), precision depletion (e.g., anti-LOX-1), and microbiome modulation. Finally, we address challenges to clinical translation-phenotypic heterogeneity, metabolic ambiguity, and the "double-edged sword" of MDSC targeting. Deeper insights into MDSC biology may help develop strategies to improve outcomes in this severe syndrome.