Yingli An, Min Li, Qingqing Bai, Wudama Cui, Hou–Yong Yu, Peng Wang, Pinning Feng, Duo Mao
ABSTRACT Immunotherapy has emerged as one of the most promising strategies for achieving complete tumor eradication. However, its effectiveness against solid tumors remains limited due to the presence of an immunosuppressive tumor microenvironment. In addition, severe side effects such as cytokine storms further constrain its clinical application. Therefore, there is an urgent need to develop efficient and controllable immunotherapeutic approaches. Herein, we report the development of a novel mitochondrial DNA‐releasing photosensitizer, MQ‐PPy, which exhibits outstanding mitochondrial localization and robust reactive oxygen species generation. Upon light irradiation, MQ‐PPy induces pronounced mitochondrial oxidative damage in tumor cells, triggering the release of immunogenic damage‐associated molecular patterns and mitochondrial DNA, which activates the cGAS‐STING signaling pathway. Meanwhile, MQ‐PPy effectively induces immunogenic cell death, thereby remodeling the tumor immune microenvironment and enhancing antitumor immune responses. In vivo studies confirmed that MQ‐PPy‐mediated photodynamic therapy significantly inhibits tumor growth and notably increases the infiltration of cytotoxic T cells within the tumor. Moreover, we demonstrated that tumor cells treated with MQ‐PPy‐mediated PDT can function as a whole‐cell vaccine, effectively establishing systemic immune memory and significantly suppressing tumor growth upon rechallenge. This study presents a promising and controllable strategy for advancing tumor immunotherapy through mitochondria‐targeted photoactivation.