Targeting mitochondria as a potential therapeutic strategy against radioresistance in cancer.

Radioresistance remains a major barrier to effective cancer therapy, contributing to tumor persistence, recurrence, and poor clinical outcomes. Increasing evidence identifies mitochondria as central regulators of radiation response through their multifaceted roles in cellular bioenergetics, redox homeostasis, mitochondrial DNA (mtDNA) maintenance, apoptotic signaling, and mitochondrial dynamics. Radioresistant tumor cells undergo profound metabolic reprogramming characterized by enhanced oxidative phosphorylation (OXPHOS), glycolytic plasticity, glutaminolysis, and pentose phosphate pathway activation, enabling sustained ATP generation, antioxidant defense, and efficient DNA repair under radiation stress. In parallel, mitochondrial reactive oxygen species (ROS) signaling is tightly modulated by antioxidant systems including glutathione, superoxide dismutase, catalase, and NRF2-driven pathways, thereby limiting radiation-induced oxidative injury. Alterations in mitochondrial fusion and fission dynamics, particularly Drp1-mediated fission, further support tumor survival by promoting mitophagy, metabolic adaptation, and resistance to apoptosis. Additionally, enhanced mtDNA repair and mitochondrial biogenesis preserve mitochondrial integrity in irradiated cancer cells. Dysregulation of mitochondria-mediated intrinsic apoptotic pathways, including aberrant expression of Bcl-2 family proteins, further facilitates evasion of radiation-induced cell death. This review comprehensively examines the molecular mechanisms by which mitochondria contribute to tumor radioresistance and critically discusses emerging mitochondria-targeted therapeutic strategies aimed at improving radiosensitivity. These include OXPHOS inhibitors, glycolytic and glutaminase inhibitors, ROS-modulating agents, mitochondrial dynamics regulators, nanoparticle-based mitochondrial targeting systems, and combinatorial approaches integrating radiotherapy with immunotherapy or DNA damage response inhibitors. By integrating mechanistic insights with emerging preclinical and clinical evidence, this review highlights mitochondria as actionable therapeutic vulnerabilities and underscores the translational potential of mitochondrial-targeted radiosensitization strategies for improving outcomes in resistant malignancies.