Engineering Radiosensitizer‐Based Metal‐Phenolic Networks Potentiate STING Pathway Activation for Advanced Radiotherapy

Radiotherapy, a mainstay of first-line cancer treatment, suffers from its high-dose radiation-induced systemic toxicity and radioresistance caused by the immunosuppressive tumor microenvironment. The synergy between radiosensitization and immunomodulation may overcome these obstacles for advanced radiotherapy. Here, the authors propose a radiosensitization cooperated with stimulator of interferon genes (STING) pathway activation strategy by fabricating a novel lanthanide-doped radiosensitizer-based metal-phenolic network, NaGdF₄ :Nd@NaLuF₄ @PEG-polyphenol/Mn (DSPM). The amphiphilic PEG-polyphenol successfully coordinates with NaGdF₄ :Nd@NaLuF₄ (radiosensitizer) and Mn²⁺ via robust metal-phenolic coordination. After cell internalization, the pH-responsive disassembly of DSPM triggers the release of their payloads, wherein radiosensitizer sensitizes cancer cells to X-ray and Mn²⁺ promote STING pathway activation. This radiosensitizer-based DSPM remarkably benefits dendritic cell maturation, anticancer therapeutics in primary tumors, accompanied by robust systemic immune therapeutic performance against metastatic tumors. Therefore, a powerful radiosensitization with STING pathway activation mediated immunostimulation strategy is highlighted here to optimize cancer radiotherapy.