ABSTRACT
Radiation therapy is a primary treatment for cancer, but radioresistance remains a significant challenge in improving efficacy and reducing toxicity. Accumulating evidence suggests that deubiquitinases (DUBs) play a crucial role in regulating cell sensitivity to ionizing radiation. Traditional small-molecule DUB inhibitors have demonstrated radiosensitization effects, and novel deubiquitinase-targeting chimeras (DUBTACs) provide a promising strategy for radiosensitizer development by harnessing the ubiquitin-proteasome system. This review highlights the mechanisms by which DUBs regulate radiosensitivity, including DNA damage repair, the cell cycle, cell death, and hypoxia. Progress on DUB inhibitors and DUBTACs is summarized, and their potential radiosensitization effects are discussed. Developing drugs targeting DUBs appears to be a promising alternative approach to overcoming radioresistance, warranting further research into their mechanisms.