Myeloid-derived suppressor cells in sepsis: drivers of persistent immunosuppression and targets for precision immunotherapy.

Sepsis is a leading cause of death and long-term disability worldwide and is now recognized as a condition in which an early hyperinflammatory response rapidly transitions into a dominant and often prolonged immunosuppressive state. Among the cellular drivers of this sepsis-induced immunosuppression, myeloid-derived suppressor cells (MDSCs) have emerged as key regulators linking emergency myelopoiesis, metabolic rewiring, and adaptive immune dysfunction. In this narrative review, we summarize current knowledge on the ontogeny, phenotypic subsets, and core suppressive mechanisms of MDSCs in sepsis, including arginase- and inducible nitric oxide synthase (iNOS)-mediated amino acid depletion, reactive oxygen and nitrogen species, inhibitory checkpoint ligands, and profound metabolic and redox reprogramming. We integrate clinical and experimental data demonstrating that MDSCs expand early in sepsis and often remain elevated for weeks to months, with persistent expansion-particularly of polymorphonuclear subsets-associating with lymphopenia, impaired pathogen clearance, secondary infections, chronic critical illness, and late mortality, especially in older or comorbid patients. We further discuss animal and human models used to dissect MDSC biology, the strengths and limitations of current phenotypic and functional definitions, and the role of MDSCs as biomarkers of disease severity, susceptibility to nosocomial infections, and long-term outcomes. Finally, we review emerging therapeutic strategies that directly or indirectly target MDSCs-such as S100A8/A9 and arginase inhibition, metabolic modulation, differentiation-inducing agents, and combinations with immune checkpoint blockade or γ-chain cytokines-and outline key challenges for translating these concepts into precision immunotherapies. A deeper and more standardized understanding of MDSC heterogeneity and dynamics in sepsis will be essential to safely harness these cells as biomarkers and therapeutic targets to restore antimicrobial defense without precipitating renewed hyperinflammation.