PANoptosis in life and death across cell types: From innate immunity to therapeutic implications

Innate immune cell death is a fundamental mechanism used by organisms to respond to perturbations, including infection, tissue damage, and cancer. However, excessive cell death can be inflammatory and cause pathology. PANoptosis has emerged as a distinct, lytic, inflammatory cell death pathway initiated by innate immune sensors and driven by caspases and receptor-interacting protein kinases through multiprotein PANoptosome complexes. Genetic, biochemical, and imaging evidence initially identified PANoptosis in macrophages but now indicates that it operates across diverse immune, non-immune, and cancer cell types, where it drives host defense, inflammation, and pathology. In this review, we critically evaluate current evidence for PANoptosis as a unique and central cell death pathway across cell types and disease contexts, elucidating the key molecular mechanisms that govern its activation. We discuss emerging insights into PANoptosome biology, the physiological and pathological functions of PANoptosis, and how cell type-specific regulation shapes disease outcomes. Finally, we highlight the therapeutic opportunities and challenges associated with the cell-selective modulation of PANoptosis to improve treatment of infectious, inflammatory, and malignant diseases.