Autophagic Flux Blockade and Endoplasmic Reticulum Stress as Convergent Drivers of T Cell Apoptosis in Sepsis-Induced Immunosuppression

Background: Most deaths from sepsis now occur during the immunosuppressive phase rather than the initial cytokine storm, and apoptotic depletion of T lymphocytes is the cellular hallmark of this state. Yet the stress mechanisms that commit septic T cells to death remain split between two literatures: impaired autophagy and sustained endoplasmic reticulum stress. Main body: This narrative review integrates the two pathways into a single interconnected stress network. In septic T cells, autophagic flux is blocked at both ends: hyperactivation of the mechanistic target of rapamycin (mTOR) suppresses the ULK1 initiation complex and the class III phosphoinositide 3-kinase PIK3C3/VPS34, compromising autophagosome nucleation, while lysosomal dysfunction impairs autophagosome–lysosome fusion and clearance. In parallel, defective selective autophagy of the endoplasmic reticulum (ER-phagy) fails to clear damaged ER, so the unfolded protein response persists and switches from an adaptive to a terminal, pro-apoptotic phase through the PERK–eIF2α–ATF4–CHOP pathway. The pathways converge at shared nodes—mTOR, PIK3C3/VPS34, reactive oxygen species, calcium transfer at mitochondria-associated ER membranes, and AMP-activated protein kinase—forming one druggable axis rather than two parallel lesions. In experimental sepsis, T cell-specific autophagy deficiency aggravates apoptosis and mortality, whereas mTOR inhibition restores autophagosome–lysosome fusion and rescues CD4+ T cells; pharmacological blockade of ER stress is likewise protective. Each node yields a quantifiable pathway activity that could serve as a biomarker for immune-endotype stratification, complementing bedside cues such as lymphocyte counts and checkpoint expression. Building on clinical precedents—recombinant interleukin-7 in the randomized IRIS-7 trial and the Phase 1b study of the anti-PD-1 antibody nivolumab—we appraise strategies that restore the autophagy–ER stress balance, including mTOR inhibitors, ER stress modulators, and autophagy inducers, and outline an agenda of direct flux measurement in patients' T cells, in vivo causal-hierarchy testing, and endotype-stratified trials. The review synthesizes 92 references published between 1999 and 2026; no systematic search or meta-analysis was performed. Conclusions: Autophagic flux blockade and unresolved endoplasmic reticulum stress are two facets of one stress network driving T cell apoptosis in sepsis. This axis is druggable: biomarker-stratified interventions against it could turn supportive care into precision immunomodulation for sepsis-induced immunosuppression.