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

Abstract

AbstractPharmacological 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.