BACKGROUND: Sepsis is a life-threatening syndrome with complex pathophysiology and great clinical heterogeneity, which complicates the delivery of personalized therapies. Our goal was to demonstrate that some biomarkers identified as regulatory immune checkpoints in preclinical studies could guide the stratification of patients with sepsis into subgroups with shared characteristics of immune response or survival outcomes. METHODS: We assayed the soluble counterparts of 12 biomarkers of immune response in 113 internal medicine patients with bacterial sepsis. RESULTS: IL-1 receptor-associated kinase M (IRAK-M) exhibited the highest hazard ratios (HRs) for increased 7-day (1.94
95% confidence interval [CI], 1.17-3.20) and 30-day mortality (1.61
95% CI, 1.14-2.28). HRs of IRAK-M and galectin-1 for predicting 1-year mortality were 1.52 (95% CI, 1.20-1.92) and 1.64 (95% CI, 1.13-2.36), respectively. Patients with elevated serum levels of IRAK-M and galectin-1 had clinical traits of immune suppression and low survival rates. CONCLUSIONS: Two inhibitory immune checkpoint biomarkers (IRAK-M and galectin-1) helped identify 3 distinct sepsis phenotypes with distinct prognoses. These biomarkers shed light on the interplay between immune dysfunction and prognosis in patients with bacterial sepsis and may prove to be useful prognostic markers, therapeutic targets, and biochemical markers for targeted enrollment in therapeutic trials.