Crosstalk between mitophagy and metabolism in cancer: Mechanisms and therapeutic opportunities

Mitophagy is a highly selective autophagic process that eliminates dysfunctional mitochondria to enforce stringent cellular quality control, acting as a context-dependent modulator of stress adaptation in cancer cells. Concurrently, to thrive in hostile microenvironments, cancer cells undergo extensive metabolic reprogramming to fulfill the immense bioenergetic and anabolic demands of rapid proliferation. Rather than operating independently, mitophagy and metabolism are intrinsically coupled to form a highly sophisticated and bidirectional regulatory circuit. Metabolic disturbances trigger mitophagy, while mitophagy reciprocally remodels metabolic landscape. This crosstalk functions as a critical metabolic rheostat, equipping cancer cells with the dynamic plasticity required to cope with the dynamic physicochemical stresses. Furthermore, this mitophagy-metabolism crosstalk extends beyond cancer cells into the tumor microenvironment, orchestrating systemic metabolic symbiosis and driving immune evasion. In this review, we summarize the molecular mechanisms underpinning this crosstalk, and highlight how therapeutic targeting of these vulnerabilities offer opportunities for overcoming therapeutic resistance and improving clinical outcomes.