Autophagy determines the fate of immune cells by regulating metabolic remodeling and PANoptosis (Review).

Autophagy, as a core mechanism for maintaining cellular homeostasis, influences differentiation and functional activation of immune cells by regulating metabolic reprogramming. Crucially, autophagy serves as a molecular switch that precisely modulates differentiation and subsequent cell fate decisions. It achieves this by eliminating intracellular danger signals or key complexes, thereby determining whether immune cells undergo PANoptosis, an inflammatory death mode that integrates features of pyroptosis, apoptosis and necroptosis. The present review systematically discusses the regulatory role of autophagy in the developmental, differentiation and metabolic pathways of various immune cells. Furthermore, it elucidates the mechanistic details by which autophagy, and particularly mitophagy, dampens excessive PANoptosis activation through the elimination of danger signals (such as mitochondrial DNA and reactive oxygen species) or the degradation of PANoptosome components. Additionally, it clarifies the molecular mechanism by which autophagy dysregulation, induced by specific pathological conditions, leads to inflammatory responses and immunopathological damage. Overall, this review establishes the significance of the autophagy‑PANoptosis axis in the development and progression of autoimmune diseases and tumors, providing a solid theoretical foundation for the optimization and innovation of therapeutic strategies for these diseases.