Tumor Microenvironment Reprogrammed Bimetallic Hybrid Nanostimulator for Triggering Radio‐Cuproptosis‐Immunotherapy

Abstract Radio‐immunotherapy driven by radiation‐induced immunogenic cell death (ICD) is emerging as a potential opportunity to address conventional radiotherapy (RT) that is only applicable to localized tumor treatment. However, the effective activation of ICD during RT is severely limited by radiation dose, weak tumor immunogenicity, and radio‐resistance caused by tumor microenvironment (TME). Herein, a novel bimetallic hybrid nanoscale coordination nanostimulator is first proposed by phosphate backbone doped with copper ions (Cu 2+ ) and hafnium ions (Hf 4+ ), and then modified with polyvinylpyrrolidone (PVP). The PVPylated Cu/Hf‐doped phosphate nanostimulator (denoted as CHP) exhibits effective reprogramming of TME, including depletion of tumor endogenous glutathione (GSH), relief of tumor hypoxia and repolarization of M2 phenotypic macrophages, thus achieving tumor radiosensitization at low X‐ray irradiation dose, gradually accumulation of tumor endogenous reactive oxygen species (ROS) and augmenting cuproptosis. In addition, cuproptosis can amplify RT‐induced anti‐tumor immunity through ICD activation, ultimately resulting in a robust anti‐tumor immune response and long‐term immunity, evidenced by distant tumor growth inhibition of 4T1‐tumor‐bearing models. More interestingly, it is discovered that CHP‐mediated cuproptosis can be intensifiable during X‐ray irradiation. Taken together, this work presents a novel radio‐cuproptosis‐immunotherapy cascade strategy, offering a new perspective for innovation in the treatment field of breast cancer.