Thermoradiotherapy-Driven Enhancement of Cuproptosis by Copper-Nitroimidazole Based Nanoparticles.

Introduction: Cuproptosis, a novel form of cell death tied to copper homeostasis and protein lipoylation, holds significant promise for breast cancer treatment. However, its efficacy is severely hindered by the tumor microenvironment (TME) heterogeneity, such as hypoxia and elevated glutathione (GSH) levels. Methods: Herein, we synthesized CuNI nanoparticles via a facile hydrothermal method, which could serve as both a copper carrier and a photothermal agent, to enhance the accumulation of copper in tumor site. Following intravenous injection, CuNI accumulated and persisted in tumors via the enhanced permeability and retention effect (EPR) effect. Subsequent gradient 808 nm laser irradiation and radiotherapy (RT) were administered, CuNI could convert light energy to heat energy, which could alleviate hypoxia TME, while RT further depleted GSH and synergistically generates reactive oxygen species (ROS) with CuNI, synergistically amplifying CuNi-mediated cuproptosis. Results: This co-treatment triggered immunogenic cell death (ICD), activating dendritic cells and T-cell responses to reverse the "cold" immune microenvironment. In vivo studies demonstrated complete tumor suppression with no overt toxicity. Conclusion: The CuNI + NIR + RT strategy, leveraging "cuproptosis/ICD synergy", offers a novel paradigm for the clinical translation of cuproptosis in breast cancer.