Immune Checkpoints in Sepsis and the Path Toward Precision Immunotherapy

BACKGROUND/OBJECTIVE: Sepsis remains a leading cause of mortality worldwide, with immune dysfunction serving as a central driver of adverse outcomes. While early hyperinflammation contributes to organ damage, subsequent immunoparalysis characterized by T-cell exhaustion, monocyte deactivation, and impaired pathogen clearance accounts for late deaths and susceptibility to secondary infections. Immune checkpoint molecules have emerged as critical mediators of sepsis-induced immunosuppression. METHODS: We reviewed current literature on inhibitory checkpoint pathways including PD-1/PD-L1, CTLA-4, TIM-3, LAG-3, TIGIT, and BTLA in sepsis-induced immune dysfunction. Cell-type-specific expression patterns, dual protective and pathological roles of checkpoint signaling depending on timing and tissue context, and convergence with metabolic and epigenetic reprogramming sustaining immunoparalysis were analyzed. Myeloid checkpoints such as CD47-SIRPα and MerTK contributing to innate immune dysfunction were evaluated. RESULTS: Checkpoint molecules exhibit context-dependent roles with protective and pathological effects varying by timing and tissue microenvironment. Monocyte HLA-DR and ferritin were identified as actionable biomarkers for patient phenotyping. The ImmunoSep trial provides proof-of-concept evidence demonstrating improved outcomes with phenotype-guided immunotherapy. CONCLUSIONS: Successful translation of checkpoint-based immunotherapies requires precision medicine frameworks matching the right intervention to the right patient at the right time. Combination immunotherapies hold promise when guided by biomarker-driven stratification.