NIR‐Triggered Metal‐Polyphenol Nanoparticles Enhance HPV‐Driven Cancer Immunotherapy via Immunogenic Cell Death and STING Sequential Activation

Abstract HPV‐associated malignancies consistently express E6/E7 oncoproteins, making these viral antigens prime targets for therapeutic vaccination. However, insufficient antigen exposure and presentation remain major obstacles for potent immunotherapy. Here, a novel metal‐polyphenol network‐coated human serum albumin nanoplatform (IMT@H) is engineered to co‐deliver IR780 and manganese ions (Mn 2+ ) to achieve enhanced immunogenic cell death (ICD) and cGAS‐STING‐dependent antigen presentation. The metal‐polyphenol nanostructure facilitates the pH‐responsive release of Mn 2+ , which subsequently initiates Fenton‐like reactions to generate hydroxyl radicals (·OH). Meanwhile, under near‐infrared (NIR) light irradiation, IR780 induces mitochondrial‐targeted phototherapy and concurrently produces reactive oxygen species (ROS). These processes act synergistically to amplify the oxidative damage and ICD in TC‐1 tumors, leading to the release of damage‐associated molecular patterns (DAMPs). These ICD‐derived DAMPs cooperate with Mn 2+ to sustain activation of the cGAS‐STING pathway in dendritic cells. This combinatorial strategy successfully transforms tumor antigens into endogenous vaccines, eventually inhibiting the growth of primary tumors and producing strong abscopal effects. Notably, mice primed with nanovaccines exhibit strong anti‐HPV16 E7‐specific immune responses and tumor resistance. With its dual therapeutic and preventive functionality, IMT@H represents a paradigm‐shifting strategy for virus‐driven malignancies and offers a blueprint for engineering self‐adjuvanting nanovaccines against viral oncogenesis.