A Robust Mitochondria‐Targeted Photosensitizer Synergizes With Cisplatin Chemotherapy for Enhanced Antitumor Immunity

ABSTRACT

Chemotherapy remains a major strategy for cancer treatment, with cisplatin widely used as a first‐line agent for diverse malignancies. Although cisplatin efficiently induces tumor cell death through DNA damage, its therapeutic efficacy is often limited by the development of an immunosuppressive tumor microenvironment that restricts effective immune activation. Here, we report a rationally engineered photosensitizer, CMPE, featuring efficient reactive oxygen species (ROS) generation and precise mitochondrial targeting. Upon spatially controlled light activation, CMPE induces mitochondrial oxidative stress and, in combination with cisplatin, triggers potent immunogenic cell death accompanied by robust release of damage‐associated molecular patterns that promote immune cell maturation and activation. In vivo, CMPE in combination with cisplatin enhances CD8 ⁺ T‐cell infiltration while reducing immunosuppressive cell populations, thereby converting immunologically “cold” tumors into an immune‐active phenotype and ultimately leading to significant tumor growth inhibition. Moreover, tumor cells pretreated with CMPE, either alone or combined with cisplatin, function as an effective whole‐cell vaccine that elicits durable immune memory and suppresses tumor recurrence. These findings demonstrate that a mitochondria‐targeted photosensitizer can serve as an effective platform for synergistic chemo‐photodynamic immunotherapy.