Mitochondrial metabolic reprogramming drives tumor immune evasion: regulatory mechanisms and targeting strategies

Cancer immunotherapy leverages the host’s immune system to combat malignant tumors, revolutionizing the field of oncology. However, drug resistance in tumor immunotherapy, which leads to attenuated efficacy or even treatment failure, remains a major challenge in clinical practice. Cancer cells rely on metabolic reprogramming to fulfill their escalating energy and biosynthetic demands. As the central organelles governing cellular energy metabolism, mitochondria play a prominent role in modulating immune cell metabolism and activation, as well as mediating tumor immune escape and therapeutic resistance. Emerging evidence indicates that targeting mitochondria-related pathways can boost the immunogenicity and antigen-presentation efficiency of tumor cells, enhance immune effector functions, and promote tumor cell killing, thereby offering a novel strategy for overcoming immunotherapy resistance. This review systematically summarizes the core functions of mitochondria in tumor immune regulation, with a focus on the molecular mechanisms underlying mitochondria-mediated immunotherapy resistance. We further discuss mitochondria-targeted interventions that reverse such resistance, along with their translational and clinical potential. By integrating the latest research advances, this review provides theoretical insights and a conceptual framework for future mechanistic studies and clinical translation.