Cytokine release syndrome: Inflammatory signaling, panoptosis, and therapeutic perspectives

Cytokine release syndrome (CRS) is a major limitation of current immunotherapy. Inflammatory complications are prone to occur after chimeric antigen receptor T-cell therapy and other immune-binding strategies. Cytokine overproduction is a well-defined feature of CRS. Yet the progression of CRS involves a complex interplay between immune activation, inflammatory cell death, endothelial dysfunction, and tissue damage. PANoptosis is a form of cell death that integrates pyroptosis, apoptosis, and necroptosis mechanisms. This review discusses the role of PANoptosis in the pathogenesis of CRS and highlights the reciprocal regulation between inflammatory signaling and cell death programs. Cytokine-mediated cellular reprogramming and innate immune activation promote PANoptotic responses. The inflammatory mediators and injury-related signals released by dying cells further aggravate immune activation and tissue damage. These processes lead to the persistence and amplification of CRS. Current and emerging therapeutic approaches targeting cytokine signaling, inflammatory pathways, and PANoptotic modulation are also discussed. Understanding the interplay of cytokine signaling and inflammatory cell death in CRS may provide a more complete perspective for studying disease progression and developing mechanism-directed interventions.