Research progress on the interconnected network of mitophagy and energy metabolism in tumors

Abstract As hallmarks of tumors, mitophagy and energy metabolic reprogramming have drawn extensive research interest. Under acute stress, cells initiate mitophagy via ubiquitination-dependent or ubiquitination-independent pathways to maintain oxidative phosphorylation (OXPHOS) efficiency. Under metabolic conditions such as hypoxia, glycolysis becomes the primary source of energy. In addition, the AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR) energy-sensing axis and metabolites such as succinate can regulate the activation threshold and efficiency of mitophagy by sensing the state of energy metabolism. A substantial body of evidence has demonstrated that mitophagy and energy metabolism jointly drive malignant tumor progression. Together, they not only enable tumor cells to survive in extreme environments such as hypoxia and nutrient deprivation, thereby endowing cancer stem cells (CSCs) with metabolic plasticity and treatment tolerance, but also induce systemic immune evasion by reshaping the immunosuppressive microenvironment. Nevertheless, the integrated function of this bidirectional network and its systemic impacts on tumor progression remain still unclear. In this review, we adopt a pan-cancer perspective to systematically dissect the molecular underpinnings, functional convergence, and preclinical translational potential of the bidirectional regulatory network linking mitophagy and energy metabolism. We also consider how emerging dynamic imaging technologies, multi-omics integration, and organoid models may promote a major shift from network analysis to precise regulation, providing preclinical rationale to develop therapies that overcome tumor therapeutic resistance in future translational investigations.