Dual-Activating Pyroptosis and cGAS-STING Pathway for Immuno-Photodynamic Therapy Based on a Thermally Activated...

Immunotherapy has emerged as a cornerstone of cancer treatment, yet its efficacy is often limited by the immunosuppressive tumor microenvironment, which is marked by low immunogenicity and insufficient cytotoxic T cell infiltration. To address these challenges, we have developed an innovative thermally activated delayed fluorescence (TADF)-based photosensitizer, termed TA2O. Leveraging its advantageous TADF properties, including a small singlet-triplet energy gap and prolonged triplet state lifetime, TA2O efficiently generates reactive oxygen species (ROS) upon light irradiation. This process triggers caspase‑1/GSDME‑dependent pyroptosis, leading to the release of tumor-associated antigens and damage-associated molecular patterns that stimulate adaptive immunity. Concurrently, the accumulation of cytosolic DNA activates the cGAS-STING pathway, thereby bolstering innate immune responses. Both in vitro and in vivo studies demonstrate that TA2O effectively eradicates tumor cells, promotes dendritic cell (DC) maturation, facilitates cytotoxic T lymphocyte infiltration, and induces a marked M2-to-M1 macrophage polarization, effectively promoting immune infiltration and inflammatory remodeling of the tumor microenvironment. Moreover, a combinatorial strategy integrating TA2O-mediated photodynamic therapy with anti-PD-1 immune checkpoint blockade (ICB) exhibits superior antitumor efficacy compared to either monotherapy. This immuno-phototherapeutic approach represents a promising advance in precision cancer immunotherapy.