Endoplasmic Reticulum-Targeting AIE Photosensitizers to Boost Immunogenic Cell Death for Immunotherapy of Bladder Carcinoma

Bladder cancer is characterized by high rates of recurrence and multifocality. Immunogenic cell death (ICD) of cancer cells has emerged as a promising strategy to improve the immunogenicity of tumor cells for enhanced cancer immunotherapy. Although photosensitizer-based photodynamic therapy (PDT) has been validated as capable of inducing ICD in cancer cells, the photosensitizers with a sufficient ICD induction ability are still rare, and there have been few reports on the development of advanced photosensitizers to strongly evoke the ICD of bladder cancer cells for eliciting potent antitumor immune responses and eradicating bladder carcinoma in situ. In this work, we have synthesized a new kind of endoplasmic reticulum (ER)-targeting aggregation-induced emission (AIE) photosensitizer (named DPASCP-Tos), which could effectively anchor to the cellular ER and trigger focused reactive oxygen species (ROS) production within the ER, thereby boosting ICD in bladder cancer cells. Furthermore, we have demonstrated that bladder cancer cells killed by ER-targeted PDT could serve as a therapeutic cancer vaccine to elicit a strong antitumor immunity. Prophylactic vaccination of the bladder cancer cells killed by DPASCP-Tos under light irradiation promoted the maturation of dendritic cells (DCs) and the expansion of tumor antigen-specific CD8⁺ T cells in vivo and protected mice from subsequent in situ bladder tumor rechallenge and extended animal survival. In summary, the ER-targeted AIEgens developed here significantly amplified the ICD of bladder cells through focused ROS-based ER oxidative stress and transformed bladder cancer cells into the therapeutic vaccine to enhance immunogenicity against orthotopic bladder cancer, providing valuable insights for bladder carcinoma treatment.