Therapeutic Promise of Mitophagy in Cancer: Advancing from Small-Molecule Regulation to Nanotechnology-Enhanced Targeting Therapy

Mitophagy, a selective autophagic pathway that clears damaged or dysfunctional mitochondria, has emerged as a promising therapeutic approach. Mitophagy maintains a delicate balance between cell survival and death, while mounting evidence suggests that it predominantly promotes tumor cell survival under stress, particularly in responses to cancer therapy. Moreover, aberrant regulation of mitophagy results in cancer pathology with characteristic hallmarks, including remodeling of metabolic plasticity, maintenance of cancer stem cell characteristics, and immune regulation of the tumor microenvironment. This review synthesizes multifaceted roles of mitophagy in cancer biology, from tumor initiation and progression to therapy responses. It also summarizes molecular mechanisms underlying mitophagy. How cancer cells exploit mitophagy to survive therapy has been harnessed to develop therapeutic strategies. We elaborate the evolution of mitophagic therapy from small-molecule modulators to nanotechnology-based targeted delivery systems. Finally, we highlight the promise of targeting mitophagy in overcoming treatment resistance and improving clinical outcomes for patients.