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

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. To activate the systemic anti-tumor immunity, photodynamic nanoparticles with potent Toxic platinum (NPPDT-56MESS) are successfully prepared. NPPDT-56MESS activates the cGAS-STING pathway via ROS and 56MESS released upon irritated by a NIR laser (NPPDT-56MESS +L). Furthermore, NPPDT-56MESS + L eradicates tumors and dramatically inhibits the recurrence and metastasis of tumors in mice.image