| Abstract Ionizing radiation exerts its biological effects primarily through the induction of DNA damage, particularly DNA double-strand breaks (DSBs). Activation of the DNA damage response (DDR) regulates cell-cycle arrest, DNA repair, apoptosis, and cellular senescence, thereby contributing to tumor control. However, recent studies have shown that radiation-induced cellular responses extend beyond DNA damage. Reactive oxygen species (ROS), lipid peroxidation, metabolic reprogramming, and extracellular vesicle-mediated intercellular communication also influence cell fate and therapeutic outcomes. These biological responses are strongly influenced by radiation quality. Low-linear energy transfer (LET) radiation, such as X-rays and γ-rays, mainly induces dispersed DNA damage, whereas high-LET radiation, including carbon-ion beams, generates clustered and complex DNA damage that is considerably more difficult to repair. Furthermore, ultra-high dose-rate (FLASH) irradiation has emerged as a promising approach that maintains tumor control while reducing normal tissue toxicity. Radiation quality and dose rate therefore influence not only DNA damage but also oxidative stress, redox homeostasis, and intracellular signaling. Recent attention has focused on non-canonical forms of radiation-induced cell death. Ferroptosis, an iron-dependent regulated cell death driven by lipid peroxidation, has emerged as a determinant of radiosensitivity and a potential therapeutic target for apoptosis-resistant tumors. Ionizing radiation can also modulate anoikis, cell adhesion signaling, cytoskeletal organization, and epithelial–mesenchymal plasticity, thereby influencing tumor invasion and metastatic potential. This lecture will provide an overview of the diverse cellular responses to ionizing radiation, focusing on DNA damage responses, the biological effects of radiation quality, and emerging mechanisms of radiation-induced cell death and metastasis suppression. |
