In a study published in Nature Nanotechnology, Prof. GU Zhanjun from the Institute of High Energy Physics of the Chinese Academy of Sciences, in collaboration with Dr. YAN Junfang and Dr. ZHANG Fuquan from Peking Union Medical College Hospital, discovered that cuproptosis may serve as a new target for radiosensitization in re-irradiation.

In cancer treatment, patients who undergo secondary radiotherapy often face the dual challenge of acquired radiation resistance in tumor cells and weakened physical condition, making re-irradiation a significant clinical challenge. This is especially true for advanced cancer patients and elderly individuals who have a pressing need for radiosensitizing drugs during clinical radiotherapy.

Prof. GU’s team found, for the first time, that cuproptosis-related proteins in tumor tissues were highly expressed under X-ray irradiation. The research also revealed a novel cell death mechanism induced by copper ions—cuproptosis—which could serve as a new target for radiosensitization. 

Based on this finding, researchers designed and synthesized a copper-containing polyoxometalate, PWCu, to act as a targeted radiosensitizer for re-irradiation. 

PWCu nanocapsules can enter tumor cells, where they release copper ions during radiotherapy to trigger cuproptosis. In this way, the tumors’ acquired radiation resistance is overcome. In addition, the nanocapsules can activate an abscopal effect, inducing immunogenic cell death and stimulating an antitumor immune response. 

These findings suggest that PWCu nanocapsules not only enhance the local antitumor effects of radiotherapy but also activate systemic antitumor immunity. The potential of using PWCu nanocapsules to improve patient outcomes, especially in the context of recurrent and metastatic disease, is immense.

In addition, the team established advanced analytical methods using synchrotron radiation to study the oxidation states, biological distribution, and metabolic transformation of copper ions in tumor tissues, providing direct methodological support for research on structure-function relationships and metabolic processes of copper drug-based radiosensitizers, which is essential for preclinical safety and pharmacokinetic evaluation.

In summary, this study offers a new solution to the clinical challenge of re-irradiation in cancer patients, with significant academic significance and promising clinical applications.

Re-irradiation sensitization mediated by copper-containing nanocapsules. (Image by Prof. GU's group)