Covalent Protein-Conjugated Photosensitizer Efficiently Evokes Immunogenic Cell Death for Cancer Vaccine Preparation

Photodynamic therapy (PDT)-induced immunogenic cell death (ICD) has emerged as a promising strategy to stimulate robust antitumor immunity. However, the effectiveness of PDT-induced ICD on noncovalent photosensitizers remains suboptimal, as their oxidative capacity is influenced by limited cellular accumulation and suboptimal proximity to target tissue. In this work, we report a covalent ICD inducer, MBTP-Py, which incorporates a carbonylvinylpyridinium warhead into an aggregation-induced emission (AIE)-based photosensitizer. MBTP-Py covalently binds to amino and thiol groups on intracellular proteins with minimal cytotoxicity, thereby enhancing ROS oxidative capacity through improved cellular retention and proximity to target tissues. Upon light activation, MBTP-Py induces both ferroptosis and pyroptosis, thereby releasing damage-related molecular patterns and initiating ICD. Tumor cells treated with MBTP-Py, when used as a vaccine in animal models, significantly enhanced antitumor immune responses. Overall, this research integrates principles of covalent drugs to design a covalent ICD inducer, which promotes the development of tumor vaccines.