Mechanisms of Tumor Radiosensitization: A Perspective of Nano‐Radiotherapy

Radiotherapy (RT) is one of the cornerstones in cancer treatment, with approximately 50% of patients receiving radiation regimens annually. However, its clinical efficacy is constrained by two persistent challenges: tumor radioresistance and radiation-induced damage to healthy tissues. Recent advances in nanomedicine have yielded innovative nano-radiosensitizers capable of enhancing tumor-specific radiation dose deposition while sparing normal tissues, thereby addressing both limitations simultaneously. Previous advanced reviews have extensively covered intrinsic nanomaterial properties and physicochemical mechanisms of radiosensitization; this review systematically elucidates radiosensitization mechanisms through the lens of RT subprocesses, offering a novel framework to evaluate how specific mechanisms modulate discrete stages of radiation response. It includes increasing radiation dose deposition; lowering antioxidant system level to promote ROS production; collaborating with other ways to promote ROS production; collaborating with the production of exogenous cytotoxic substances; augmenting intrinsic radiosensitivity of cancer cells; stabilizing radiation-induced DNA lesions to suppress repair machinery; and enhancing radiogenic immunogenic cell death to strengthen antitumor immunity. Furthermore, we discuss emerging trends in nanotechnology-driven combination therapies. This systematic perspective advances the rational design of next-generation nano-radiosensitizers and informs personalized radiotherapy protocols. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.