Brachytherapy Combined with Cuproptosis-Inducing Radiosensitizer Overcomes Radioresistance in Triple-Negative Breast Cancer.

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.