Mitophagy: A key regulator of radiotherapy resistance in the tumor immune microenvironment

Abstract

Cancer remains a leading global cause of mortality, with radiation therapy (RT) as a cornerstone of treatment despite frequent radioresistance. Emerging evidence indicates that mitophagy activation contributes to adaptive radioresistance of cancer cells within the tumor microenvironment (TME). In this review, we highlight the dual role of mitophagy in modulating RT resistance and shaping the immune landscape of the TME. Mitophagy enhances cancer cell resilience by clearing radiation-damaged mitochondria, preserving metabolic homeostasis and reducing oxidative stress, while simultaneously altering the balance between immune activation and suppression within the TME. To provide mechanistic insight, we summarize key mitophagy-regulating pathways—including the PINK1/Parkin axis, BNIP3/NIX, and FUNDC1-mediated mechanisms—that respond to RT-induced mitochondrial stress and represent potential therapeutic targets. Furthermore, we explore how the interplay between mitophagy, metabolic reprogramming, and immune modulation shapes resistance not only to RT but also to immunotherapies such as immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T (CAR-T) cell therapy. Additionally, we examine how Type 2 diabetes(T2DM) mellitus impacts this process, as its associated metabolic disturbances exacerbate mitochondrial vulnerability to radiation and create an immunosuppressive milieu that compromises the tumor immune landscape. Understanding these interactions may support development of personalized therapeutic strategies for diabetic cancer patients.