A Second Near-Infrared Window-Responsive Metal–Organic-Framework-Based Photosensitizer for Tumor Immunotherapy via Synergistic Ferroptosis and STING Activation

Photodynamic therapy (PDT) holds promise as a cancer treatment modality due to its potential for enhanced therapy precision and safety. To enhance deep tissue penetration and minimize tissue adsorption and phototoxicity, developing photosensitizers activated by second near-infrared window (NIR-II) light shows significant potential. However, the efficacy of PDT is often impeded by tumor microenvironment hypoxia, primarily caused by irregular tumor vasculature. Fortunately, the stimulator of interferon genes (STING) pathway, known for immune activation, has been linked to vasculature normalization. In this study, we developed a nanoplatform (Fe-THBQ/SR) by loading a STING agonist (SR-717) into an iron-tetrahydroxy-1,4-benzoquinone (Fe-THBQ) metal-organic framework. Fe-THBQ was proven to be an effective NIR-II photosensitizer, generating numerous reactive oxygen species (ROS) under 1064 nm laser irradiation. These ROS downregulated heat shock protein expression, consequently promoting mild-photothermal therapy (mild-PTT), and facilitated ferroptosis by depleting glutathione (GSH)/glutathione peroxidase 4. Moreover, Fe-THBQ/SR released SR-717 upon GSH stimulation, synergizing with the ROS-mediated double-stranded DNA leakage to enhance STING activation. This process contributed to tumor vasculature normalization and hypoxia alleviation, thereby enhancing the PDT efficacy. Overall, we presented a versatile single-laser-triggered nanoplatform (Fe-THBQ/SR) for NIR-II PDT and NIR-II mild-PTT and simultaneously coupled it with the effective activation of STING to form a reinforcing cycle. These synergistic enhancements increased the immunogenicity of tumor cells, remodeled the immunosuppressive tumor microenvironment, increased T lymphocyte infiltration, and improved therapeutic outcomes.