cGAS‐STING Pathway Activation and Systemic Anti‐Tumor Immunity Induction via Photodynamic Nanoparticles with Potent Toxic Platinum DNA Intercalator Against Uveal Melanoma

Abstract The cGAS‐STING pathway, as a vital innate immune signaling pathway, has attracted considerable attention in tumor immunotherapy research. However, STING agonists are generally incapable of targeting tumors, thus limiting their clinical applications. Here, a photodynamic polymer (P1) is designed to electrostatically couple with 56MESS–a cationic platinum (II) agent–to form NPPDT‐56MESS. The accumulation of NPPDT‐56MESS in the tumors increases the efficacy and decreases the systemic toxicity of the drugs. Moreover, NPPDT‐56MESS generates reactive oxygen species (ROS) under the excitation with an 808 nm laser, which then results in the disintegration of NPPDT‐56MESS. Indeed, the ROS and 56MESS act synergistically to damage DNA and mitochondria, leading to a surge of cytoplasmic double‐stranded DNA (dsDNA). This way, the cGAS‐STING pathway is activated to induce anti‐tumor immune responses and ultimately enhance anti‐cancer activity. Additionally, the administration of NPPDT‐56MESS to mice induces an immune memory effect, thus improving the survival rate of mice. Collectively, these findings indicate that NPPDT‐56MESS functions as a chemotherapeutic agent and cGAS‐STING pathway agonist, representing a combination chemotherapy and immunotherapy strategy that provides novel modalities for the treatment of uveal melanoma.