Reactive Oxygen Species as Central Coordinators of Organelle Stress and Tumor Radiosensitivity

Radiotherapy is a major modality for cancer treatment, but therapeutic responses vary substantially across tumor types and patients. Beyond direct DNA damage, radiation-induced reactive oxygen species (ROS) are increasingly recognized as dynamic regulators of cellular stress responses. Their biological effects depend not only on the magnitude of ROS generation, but also on its duration, subcellular distribution, and whether antioxidant, repair, and organelle quality-control systems can contain the resulting damage. Transient oxidative stress may activate adaptive responses, whereas persistent ROS can trigger mitochondrial ROS amplification, ER stress and Ca²⁺ dysregulation, lysosomal dysfunction, iron-dependent lipid peroxidation, and irreversible cell injury. These processes are coordinated through an interconnected organelle network rather than occurring independently. ROS also exerts context-dependent effects on antitumor immunity: localized oxidative stress can promote danger-associated molecular patterns (DAMPs) release, cGAS-STING signaling, and immune activation, whereas prolonged oxidative stress may impair effector immune cells and favor immunosuppression. This review integrates these mechanisms within an organelle-level redox framework and discusses emerging strategies for improving radiotherapy and radioimmunotherapy through selective modulation of redox homeostasis, with particular attention to tumor selectivity, safety, hypoxia, and clinical translation.