The Uncovered Role of Interferons in Sepsis: From Pathogenesis to Precision Immunotherapy

Abstract: Sepsis is a life-threatening syndrome characterized by a dysregulated host response to infection resulting in organ dysfunction. While traditional paradigms have emphasized proinflammatory cytokines, such as tumor necrosis factor-α and interleukin-1β, interferons (IFNs) are increasingly recognized as critical yet underexplored mediators of sepsis pathobiology. IFNs are central regulators of innate and adaptive immunity and have emerged as key mediators of the immune alterations observed during sepsis. Type I IFNs (IFN-α/β), type II IFN (IFN-γ), and type III IFNs exert pleiotropic effects on immune activation, pathogen clearance, endothelial function, immunometabolism, and tissue injury. While early IFN responses support antimicrobial defense, sustained or dysregulated signaling contributes to hyperinflammation, endothelial dysfunction, immune exhaustion, coagulopathy, and multiorgan failure. Increasing evidence from experimental models and clinical studies suggests that IFN activity differs substantially among septic patients and may define biologically distinct immune endotypes. IFN-stimulated gene signatures and IFN-related biomarkers therefore represent promising tools for patient stratification and precision immunotherapy. This review summarizes the biology of IFNs relevant to sepsis, their role across different disease phases, their contribution to organ dysfunction, and emerging therapeutic strategies targeting IFN pathways. Current evidence supports a shift toward biomarker-guided and phase-specific immunomodulation aimed at restoring immune homeostasis while minimizing harmful inflammation.