Photochemical bomb: Precision nuclear targeting to activate cGAS-STING pathway for enhanced bladder cancer immunotherapy

Abstract

Activating the cGAS-STING pathway presents a promising strategy to enhance the innate immunity and combat the immunosuppressive tumor microenvironment. One key mechanism for triggering this pathway involves the release of damaged DNA fragments caused by nuclear DNA damage. However, conventional cGAS-STING agonists often suffer from limited nucleus-targeting efficiency and potential biotoxicity. In this study, we develop a novel nucleus-targeting theranostic nanoplatform designed to synergistically activate the cGAS-STING pathway through the combination of photodynamic therapy (PDT) and cisplatin chemotherapy for orthotopic bladder cancer treatment. The nanoplatform integrates a new high-performance type-I photosensitizer with near-infrared-II emission, a TAT^SA peptide for enhanced nuclear targeting, and a biosafe platinum (IV) cisplatin prodrug. Upon NIR laser irradiation, the nanoagent delivers synergistic nucleus-targeted PDT and chemotherapy, causing substantial DNA damage and the release of double-stranded DNA, which subsequently activates the cGAS-STING pathway and triggers potent immunomodulation. This activation promotes dendritic cells maturation, enhances cytotoxic T infiltration, and facilitates the formation of memory T cells, leading to immune microenvironment remodeling, and long-lasting immune memory, thus effectively inhibiting orthotopic bladder tumors and reducing the risk of metastasis. These findings highlight the substantial potential of this strategy to overcome the limitations of current immunotherapies by leveraging nucleus-targeted PDT to activate the cGAS-STING pathway for cancer treatment.