Efferocytosis: Signaling Pathways and New Therapeutic Strategies for Diseases

Efferocytosis-the phagocytic clearance of apoptotic cells (ACs)-is essential for maintaining tissue homeostasis, immune tolerance, and inflammation resolution. Beyond classic receptor-mediated recognition, this process drives phagocyte metabolic reprogramming to actively facilitate tissue repair. Consequently, defective efferocytosis serves as a core pathogenic mechanism across major human diseases. This review outlines the molecular and metabolic foundations of efferocytosis and defines four universal hallmarks of its dysfunction: senescence-driven impairment, unresolved inflammation, loss of immune tolerance, and fibrotic tissue repair. Subsequent sections explore how these defects manifest in cardiovascular, autoimmune, and neurodegenerative conditions, as well as cancer. Because efferocytosis exhibits a dual pathophysiological nature, therapeutic interventions must be highly disease-specific. Enhancing apoptotic clearance can effectively resolve chronic inflammatory and fibrotic conditions. Conversely, because tumors hijack these same pathways to build immunosuppressive microenvironments, inhibiting efferocytosis remains a critical strategy in oncology. The synthesis of these divergent roles informs a "context-dependent directionality" framework to guide the clinical translation of efferocytosis-targeted precision therapies.