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.