Du Hongxiang, Xu Tianhan, Yu Sihui, Wu Sufang, Zhang Jiawen
Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Obstetrics and Gynecology, Zhongshan Hospital, Fudan University, Shanghai, China.
Signal Transduct Target Ther. 2025 Aug 4;10(1):245. doi: 10.1038/s41392-025-02311-x.
Mitochondria are dynamic organelles that are essential for cellular energy generation, metabolic regulation, and signal transduction. Their structural complexity enables adaptive responses to diverse physiological demands. In cancer, mitochondria orchestrate multiple cellular processes critical to tumor development. Metabolic reprogramming enables cancer cells to exploit aerobic glycolysis, glutamine metabolism, and lipid alterations, supporting uncontrolled growth, survival, and treatment resistance. Genetic and epigenetic alterations in mitochondrial and nuclear DNA disrupt oxidative phosphorylation, tricarboxylic acid cycle dynamics, and redox homeostasis, driving oncogenic progression. Mitochondrial dysfunction in tumors is highly heterogeneous, influencing disease phenotypes and treatment responses across cancer types. Within the tumor microenvironment, mitochondria profoundly impact immune responses by modulating T-cell survival and function, macrophage polarization, NK cell cytotoxicity, and neutrophil activation. They also mediate stromal cell functions, particularly in cancer-associated fibroblasts and tumor endothelial cells. Although targeting mitochondrial function represents a promising therapeutic strategy, mitochondrial heterogeneity and adaptive resistance mechanisms complicate interventional approaches. Advances in mitochondrial genome editing, proteomics, and circulating mitochondrial DNA analysis have enhanced tumor diagnostic precision. This review synthesizes the developmental landscape of mitochondrial research in cancer, comprehensively summarizing mitochondrial structural dynamics, metabolic plasticity, signaling networks, and interactions with the tumor microenvironment. Finally, we discuss the translational challenges in developing effective mitochondria-based cancer interventions.
线粒体是动态细胞器，对细胞能量生成、代谢调节和信号转导至关重要。其结构复杂性使其能够对多种生理需求做出适应性反应。在癌症中，线粒体协调着对肿瘤发展至关重要的多个细胞过程。代谢重编程使癌细胞能够利用有氧糖酵解、谷氨酰胺代谢和脂质改变，支持不受控制的生长、存活和治疗抗性。线粒体和核DNA的遗传和表观遗传改变会破坏氧化磷酸化、三羧酸循环动力学和氧化还原稳态，推动致癌进展。肿瘤中的线粒体功能障碍高度异质性，影响不同癌症类型的疾病表型和治疗反应。在肿瘤微环境中，线粒体通过调节T细胞存活和功能、巨噬细胞极化、NK细胞细胞毒性和中性粒细胞活化，深刻影响免疫反应。它们还介导基质细胞功能，特别是在癌症相关成纤维细胞和肿瘤内皮细胞中。尽管靶向线粒体功能是一种有前景的治疗策略，但线粒体异质性和适应性抗性机制使干预方法复杂化。线粒体基因组编辑、蛋白质组学和循环线粒体DNA分析的进展提高了肿瘤诊断的准确性。本综述综合了癌症中线粒体研究的发展概况，全面总结了线粒体结构动态、代谢可塑性、信号网络以及与肿瘤微环境的相互作用。最后，我们讨论了开发有效的基于线粒体的癌症干预措施中的转化挑战。
