Mitochondria-targeted strategies in cancer radiotherapy: from ROS regulation to immunogenic cell death.

Radiotherapy (RT) is a crucial treatment modality for various solid tumors. Its antitumor effects not only depend on direct DNA damage but also involve the disruption of redox homeostasis centered around mitochondria and the activation of immune responses. Mitochondria, as a central hub for cellular energy metabolism and apoptosis signaling, serve both as the primary source of reactive oxygen species (ROS) and as key targets for ROS attack during RT. RT promotes the sustained accumulation of mitochondrial ROS (mROS) through mechanisms such as damage to the mitochondrial respiratory chain complexes, while also triggering compensatory clearance responses from antioxidant systems. The dynamic balance between these processes determines the cell's fate. Moreover, mitochondria play a crucial regulatory role in immunogenic cell death (ICD). Damage-associated molecular patterns (DAMPs) such as mitochondrial DNA (mtDNA), ATP, and cytochrome c, along with ROS-mediated endoplasmic reticulum stress and calcium signaling, promote dendritic cell (DC) maturation and induce antitumor immunity. In recent years, mitochondria-based RT sensitization strategies have emerged, including small molecules that modulate mROS production or antioxidant defenses, mitochondria-targeted nanocarriers, gene-editing approaches, and bioregulatory or metabolic interventions. Most nanoplatforms, gene-editing strategies, and ICD-amplifying approaches are currently supported mainly by preclinical evidence, where they have been shown to enhance RT-induced tumor cell death, promote DAMP release, and improve antitumor immune activation. In contrast, selected metabolic or bioregulatory interventions have begun to enter early clinical evaluation, including ketogenic dietary interventions combined with immune checkpoint blockade in metastatic melanoma and renal cell carcinoma (e.g., NCT06391099 and NCT06896552), although definitive evidence of clinical benefit in combination with RT remains limited. This review systematically discusses mitochondrial mechanisms of ROS generation and clearance during RT, mitochondrial regulation of ICD pathways, and emerging mitochondria-targeted radiosensitization strategies, while emphasizing the current distinction between preclinical promise and clinical translational maturity.