Xia Jing, Jin Jing, Dai Shuang, Fan HaoHan, Chen KeLiang, Li JianMei, Luo Feng, Peng Xingchen
Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu Sichuan, China; The Department of Obstetrics and Gynecology, West China Second University Hospital of Sichuan University, Chengdu, Sichuan, China.
Mol Aspects Med. 2025 Jul 20;105:101385. doi: 10.1016/j.mam.2025.101385.
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.
癌症仍然是全球主要的死亡原因，尽管放射抗性常见，但放射治疗（RT）仍是治疗的基石。新出现的证据表明，线粒体自噬激活有助于肿瘤微环境（TME）中癌细胞的适应性放射抗性。在本综述中，我们强调了线粒体自噬在调节放射抗性和塑造TME免疫格局方面的双重作用。线粒体自噬通过清除受辐射损伤的线粒体、维持代谢稳态和减少氧化应激来增强癌细胞的恢复力，同时改变TME内免疫激活与抑制之间的平衡。为了提供机制性见解，我们总结了关键的线粒体自噬调节途径，包括PINK1/Parkin轴、BNIP3/NIX和FUNDC1介导的机制，这些途径对RT诱导的线粒体应激作出反应，并代表潜在治疗靶点。此外，我们探讨了线粒体自噬、代谢重编程和免疫调节之间的相互作用如何不仅塑造对RT的抗性，还塑造对免疫检查点抑制剂（ICI）和嵌合抗原受体T（CAR-T）细胞疗法等免疫疗法的抗性。此外，我们研究了2型糖尿病（T2DM）如何影响这一过程，因为其相关的代谢紊乱会加剧线粒体对辐射的易损性，并创造一个免疫抑制环境，损害肿瘤免疫格局。了解这些相互作用可能有助于为糖尿病癌症患者制定个性化治疗策略。
