Mitophagy: A double-edged sword in tumor cell death regulation and therapeutic response

Abstract

Mitophagy, a core mechanism governing cellular homeostasis, plays dual roles in tumorigenesis and therapeutic response by selectively eliminating damaged mitochondria. This review systematically summarizes the molecular mechanisms of mitophagy mediated by receptor-dependent ubiquitin-independent pathways and ubiquitin-dependent pathways, and explores their intricate crosstalk with tumor cell death modalities. Mitophagy dynamically regulates mitochondrial quality to modulate the progression of apoptosis, ferroptosis, necroptosis, immunogenic cell death (ICD), and pyroptosis. Notably, mitophagy exhibits context-dependent roles in tumors: moderate activation suppresses tumor growth by clearing carcinogen-damaged mitochondria, whereas excessive activation may directly induce cell death via functional mitochondrial depletion or synergize with chemotherapy to amplify tumor eradication. Furthermore, this review highlights the challenges in therapeutic strategies targeting the mitophagy-tumor death axis, emphasizing the potential of spatiotemporal-specific regulation and combinatorial interventions across distinct death pathways, thereby providing a theoretical framework for precision oncology.