TADF-Guiding Modification of Endoplasmic Reticulum-Targeted Photosensitizers for Efficient Photodynamic Immunotherapy

Pharmacological activation of the immunogenic cell death (ICD) pathway by endoplasmic reticulum (ER) targeted photosensitizer (PS) has become a promising strategy for tumor immunotherapy. Despite a clear demand for ER-targeted PS, the sluggish intersystem crossing (ISC) process, unstable excited state, insufficient ROS production, and immunosuppressive tumor microenvironment (ITME) combined to cause the high-efficiency agents are still limited. Herein, three groups commonly used in thermally activated delayed fluorescence (TADF) molecular design are used to modify the excited state characteristics of xanthene-based cyanine PS (obtained the XCy-based PS). The electronic and geometric modulation effectively optimize the excited state characteristics, facilitating the ISC process and prolonging the excited state life for boosting ROS generation. Among them, car-XCy showed 100 times longer excited state life and 225% higher ROS yield than that of original XCy. The satisfactory ROS production and ER-targeted ability of car-XCy arouse intense ER stress to activate the ICD. Adequate antigen presentation promotes the dendritic cell maturation and infiltration of cytotoxic T lymphocytes (CTLs), ultimately reversing the ITME to realize efficient immunotherapy. As a result, significant inhibition is observed in both primary and distant tumors, underscoring the efficacy of this TADF-guiding excited state characteristics modulation strategy for developing photodynamic immunotherapy drugs.