Dual‐Activating Pyroptosis and cGAS‐STING Pathway for Immuno‐Photodynamic Therapy Based on a Thermally Activated Delayed Fluorescence Photosensitizer

ABSTRACT 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.