Oxygen-driven cuproptosis synergizes with radiotherapy to potentiate tumor immunotherapy

The immunological implications of cuproptosis, a form of cell death highly sensitive to oxygen presence, remain largely unexplored in the context of tumor immunotherapy. Herein, we initially investigate the positive correlation between cuproptosis and tumor immunotherapy through bioinformatics analysis. Subsequently, an oxygen generator loaded with copper ions (^Cu/APH-M) has been constructed, which serves as an effective carrier of copper ions and crucially enhances the oxygenation of the tumor microenvironment. Importantly, ^Cu/APH-M-mediated dual strengthening of cuproptosis and radiotherapy could not only trigger a powerful antitumor immunity related to immunogenic cell death by RNA-sequencing analysis, but also effectively inhibit the growth of both distal and in situ low rectal tumors after combined immunotherapy, creating a robust immune memory effect. Our work reveals the beneficial effects of enhanced cuproptosis in radio-immunotherapy and elucidates its underlying mechanisms, which provides a novel approach for the synergistic integration of cuproptosis with immunotherapy and radiotherapy, broadening the scope of cuproptosis-mediated tumor therapy.