Cell death mechanisms in sepsis-associated adaptive immune dysfunction

Sepsis remains a leading cause of death, driven not only by early hyperinflammation but also by a catastrophic collapse of adaptive immunity during the late phase. This failure is orchestrated by distinct regulated cell death (RCD) pathways - apoptosis, pyroptosis, necroptosis and ferroptosis - that differentially deplete T cells, B cells and dendritic cells while shaping the immunological milieu. Apoptosis silently eliminates lymphocytes and promotes immunosuppression; pyroptosis and necroptosis release damage-associated molecular patterns, fueling inflammation that paradoxically destroys adaptive effectors; and ferroptosis, an iron-dependent lipid peroxidation process, selectively targets metabolically active CD8⁺ and T helper cells. This review proposes that these pathways do not operate in isolation but converge on a "cell death decision network" centred on caspase-8, receptor-interacting serine/threonine-protein kinase 1(RIPK1), reactive oxygen species (ROS) and mitochondria, whose integration determines lymphocyte fate under septic stress. Understanding this network opens opportunities for precision immunotherapy. Emerging strategies targeting these pathways hold promise, but their success will require phase-specific application, biomarker-guided patient stratification and cell-type-selective delivery. Targeting the quality, as well as the quantity, of cell death may restore adaptive immunity and improve survival in sepsis.