Brachytherapy Combined with Cuproptosis-Inducing Radiosensitizer Overcomes Radioresistance in Triple-Negative Breast Cancer
Xue Wang, Chenglu Gu, Jie Zhang, Xihong Guo, Shuang Zhu, Shuanglong Du, Chen Yang, Fuquan Zhang, Chunli Luo, Xilin Yang, Xiuxiu Wang, Jingjing Tian, Jiawei Zhu, Zheng Zeng, Junfang Yan, Baoyun Sun, Zhanjun GuAbstract
Acquired radioresistance remains a major clinical obstacle in triple-negative breast cancer (TNBC) radiotherapy. Here, we first report the combined use of an ultrasmall copper-doped hafnium oxide nanoradiosensitizer (US-HfO2:Cu, ∼10 nm) and 192Ir brachytherapy (BT) to address this issue. BT triggers radiation-responsive Cu+ release from US-HfO2:Cu, inducing intracellular copper overload and cuproptosis, while the high-Z HfO2 core enhances radiation energy deposition to aggravate DNA damage. This synergistic biophysical strategy impairs mitochondrial function and activates the cGAS-STING pathway, eliciting immunogenic cell death and robust systemic antitumor immunity. When combined with brachytherapy, US-HfO2:Cu efficiently suppresses primary tumor growth and inhibits distant tumor metastasis via the abscopal effect in the acquired radioresistant TNBC murine model, while minimizing damage to normal tissues. These findings establish a strategy integrating cuproptosis, physical radioenhancement, and immune activation to combat aggressive radioresistant TNBC, holding great clinical translation potential.