Cuproptosis may serve as a new target for radiosensitization in Re-irradiation. This discovery, led by Prof. GU Zhanjun from the Institute of High Energy Physics of the Chinese Academy of Sciences, in close collaboration with Dr. YAN Junfang and Dr. ZHANG Fuquan from the Radiotherapy Department of Peking Union Medical College Hospital, was published in Nature Nanotechnology on Sept. 19.

In the field of cancer treatment, patients who undergo secondary radiotherapy often face the dual challenge of acquired radiation resistance in tumour 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.

With the support of a research project established at the Chinese Academy of Sciences based on synchrotron radiation facilities, Prof. GU’s team for the first time found that cuproptosis-related proteins in tumour tissues were highly expressed under X-ray irradiation, revealing a novel cell death mechanism induced by copper ions – cuproptosis, which could serve as a new target for radiosensitization. Building on this finding, the researchers designed and synthesized a copper-containing polyoxometalate, named PWCu, as a targeted radiosensitizer for re-irradiation. These nanocapsules can enter tumour cells, release copper ions during radiotherapy to trigger cuproptosis, overcoming acquired radiation resistance in tumours. Additionally, they can activate an abscopal effect, inducing immunogenic cell death and stimulating an antitumour immune response. This suggests that the PWCu nanocapsules offer a multifaceted strategy that not only enhances the local antitumour effects of radiotherapy but also activates systemic antitumour immunity (Figure 1). The potential of this approach to improve patient outcomes, especially in the context of recurrent and metastatic diseases, is immense.

Figure 1. Re-irradiation sensitization mediated by copper-containing nanocapsules. (Image by GU Zhanjun's group)

More importantly, the team established advanced analytical methods using synchrotron radiation facilities to study the oxidation states, biological distribution, and metabolic transformation of copper ions within tumour tissues (Figure 2), providing direct methodological support for the research on structure-function relationships and metabolic processes of cupper drug-based radiosensitizers, which is essential for preclinical safety and pharmacokinetic evaluation.

Figure 2. (a) Intratumoral distribution analysis of PWCu by SR-μCT; (b) H&E and SR-μXRF images of Cu and W elements in tumor tissue of mice before and after PWCu administration with radiotherapy. (Image by GU Zhanjun's group)

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