Near-Infrared II Photoactivatable Prodrug Enables Tumor-Specific Stimulator of Interferon Genes Activation for Synergistic Photodynamic Immunotherapy

The stimulator of interferon genes (STING) pathway is a promising target for cancer immunotherapy, but systemic activation often induces severe toxicity and cytokine storms. To overcome this challenge, we developed a near-infrared II (NIR-II) photoactivatable prodrug, HTAM, for targeted STING activation in the “cold” tumor microenvironment of triple-negative breast cancer. HTAM integrates a mitochondria-targeted photosensitizer (HD) with the STING agonist MSA-2 via a reactive oxygen species (ROS)-cleavable thioacetal-diol linker, enabling efficient tumor targeting and accumulation. Upon 808 nm laser irradiation, HD-generated ROS trigger linker cleavage and spatiotemporally controlled MSA-2 release at the tumor site, thereby activating the STING pathway while minimizing off-target effects. Concurrently, the photodynamic therapy induces DNA damage and immunogenic cell death, amplifying STING signaling and type I interferon production. This synergistic strategy promotes dendritic cell maturation, enhances cytotoxic T lymphocyte infiltration, and effectively reprograms the immunosuppressive microenvironment in the aggressive 4T1 model.