A NIR‐II Excitable Hyperbranched Conjugated Polymer‐Based Phototheranostic for Enhanced Tumor Radioimmunotherapy via Synergistic Cuproptosis and STING Activation

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ABSTRACT Radioresistance and the immunosuppressive tumor microenvironment (ITME) present formidable challenges in cancer radioimmunotherapy. Herein, we report a multifunctional nanotheranostic platform ( 1 2 5 I/Cu/BCP@HA) that integrates radiotherapy with delivery of copper ions, aiming to induce cuproptosis and mitochondrial DNA (mtDNA) release to amplify cGAS‐STING pathway activation. The 1 2 5 I/Cu/BCP@HA is constructed from an NIR‐II‐excitable hyperbranched conjugated polymer that is co‐assembled with 1 2 5 I and Cu 2 O via tyrosine coordination. Upon dual stimulation by the acidic TME and NIR‐II laser irradiation, the platform responsively releases copper ions and 1 2 5 I. The liberated copper ions deplete intracellular glutathione, catalyze hydroxyl radical generation, and trigger mitochondrial dysfunction, culminating in cuproptosis accompanied by mtDNA release. Concurrently, the platform exerts potent radiosensitizing effects, further amplifying the sustained nuclear DNA (nucDNA) damage induced by 1 2 5 I. The combined release of mtDNA and nucDNA fragments synergistically activates the cGAS‐STING pathway, promoting type I interferon secretion and immunogenic cell death (ICD). This coordinated response facilitates dendritic cell maturation, augments CD4 + /CD8 + T cell infiltration, and reverses TME immunosuppression, demonstrating robust antitumor efficacy both in vitro and in vivo. This work establishes a novel nanotheranostic strategy that synergistically integrates radiotherapy, photothermal therapy, cuproptosis, and STING pathway activation for enhanced cancer radioimmunotherapy.

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