PANoptosis in Cytokine Release Syndrome: Bridging the Gap between Inflammation and Cell Death

Cytokine Release Syndrome (CRS) is a hyperinflammatory condition triggered by infections, immunotherapies, and systemic immune dysregulation. PANoptosis, a unique form of programmed inflammatory cell death that integrates pyroptosis, apoptosis, and necroptosis, has emerged as a key contributor to CRS pathogenesis. This review explores the mechanistic role of PANoptosis in CRS, with particular emphasis on immunotherapy-induced toxicity and viral infections such as SARS-CoV-2 and influenza. PANoptosis exacerbates cytokine storms through ZBP1, NLRP3, and CASP8-mediated pathways, creating a pathological feedback loop that intensifies inflammation and promotes multi-organ damage. Current evidence suggests that modulating PANoptotic pathways, including targeting TNF-α, IFN-γ, and inflammasome components, may mitigate cytokine-driven tissue injury. Despite growing interest, the therapeutic potential of PANoptosis remains underexplored. Advancing our understanding of PANoptosis and its interaction with cytokine signaling will be critical for developing effective interventions for CRS and improving outcomes in patients undergoing immunotherapy or battling severe infections.