Chun Soohyun, An Jin, Kim Man S
Translational-Transdisciplinary Research Center, Medical Science Research Institute, Kyung Hee University Hospital at Gangdong, College of Medicine, Kyung Hee University, Seoul 05278, Republic of Korea.
Department of Medicine, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea.
Antioxidants (Basel). 2025 Aug 18;14(8):1008. doi: 10.3390/antiox14081008.
Intercellular mitochondrial transfer in the tumor microenvironment (TME) is a paradigm-shifting process that redefines cancer-T cell crosstalk. This review explores its dual nature as both a tumor immune evasion strategy and a promising therapeutic avenue. Crucially, oxidative stress acts as a key regulator, inducing tunneling nanotube (TNT) formation to facilitate this organelle exchange. Tumors exploit this by transferring dysfunctional, reactive oxygen species (ROS) generating mitochondria to T cells to induce senescence while simultaneously hijacking healthy mitochondria from T cells to empower their own metabolism. This directional exchange, quantified by computational tools like mitochondrial-enabled reconstruction of cellular interactions (MERCI), is linked to poor clinical outcomes. Transfer occurs via TNTs, extracellular vesicles, and direct contact. Conversely, the therapeutic transfer of healthy mitochondria from sources like mesenchymal stromal cells can revitalize exhausted T cells, improving chimeric antigen receptor T (CAR-T) cell efficacy. Clinical translation is guided by emerging biomarkers, including circulating mitochondrial DNA (mtDNA), mitochondrial haplogroups, and the tumor mitochondrial transfer (TMT) score. Harnessing this biological axis for next-generation immunotherapies requires overcoming challenges in transfer efficiency and standardization to effectively modulate the tumor redox landscape and immune response.
肿瘤微环境（TME）中的细胞间线粒体转移是一个范式转变的过程，它重新定义了癌症与T细胞之间的相互作用。本综述探讨了其作为肿瘤免疫逃逸策略和有前景的治疗途径的双重性质。至关重要的是，氧化应激作为关键调节因子，诱导隧道纳米管（TNT）形成以促进这种细胞器交换。肿瘤利用这一点，将产生功能失调的活性氧（ROS）的线粒体转移到T细胞以诱导衰老，同时从T细胞劫持健康线粒体以增强自身代谢。这种通过线粒体辅助的细胞间相互作用重建（MERCI）等计算工具量化的定向交换与不良临床结果相关。转移通过TNT、细胞外囊泡和直接接触发生。相反，从间充质基质细胞等来源进行健康线粒体的治疗性转移可以使耗竭的T细胞恢复活力，提高嵌合抗原受体T（CAR-T）细胞疗效。临床转化由新兴生物标志物指导，包括循环线粒体DNA（mtDNA）、线粒体单倍群和肿瘤线粒体转移（TMT）评分。利用这一生物学轴进行下一代免疫疗法需要克服转移效率和标准化方面的挑战，以有效调节肿瘤氧化还原格局和免疫反应。
