Hypoxia-related tumor radioresistance markedly impairs the efficacy of radiotherapy. Herein, a targeted radiosensitization strategy is introduced, leveraging the upregulation of gasdermin C (GSDMC) in hypoxic tumor cells, aiming to induce pyroptosis through the application of a cobalt-containing polyoxometalate-based radiosensitizer. This novel radiosensitizer is designed for the precisely controlled release of cobalt ions upon X-ray irradiation, thereby activating caspase-8 and prompting the cleavage of GSDMC. This sequence of events selectively triggers pyroptosis in hypoxic tumor cells, directly addressing radioresistance. The ensuing results highlight the enhanced radiotherapy efficacy and tumor necrosis both in vitro and in vivo models. Overall, the findings confirm the effectiveness of this strategy targeting high GSDMC expression in hypoxic tumors to induce pyroptosis for precise radiotherapy. Such findings encourage further exploration of hypoxia-driven pyroptosis to improve cancer treatment outcomes.