Photo-generating Type-I ROS and aryl radicals by mitochondrial-targeting oxime-ester photogenerator for pyroptosis-mediated anti-hypoxia photoimmunotherapy

Pyroptosis is an inflammatory form of programmed cell death with great potential in cancer immunotherapies. Photodynamic therapy (PDT) represents a promising treatment modality to trigger pyroptosis. However, the hypoxic microenvironment inside the tumors often induces limited therapeutic efficacy. Herein, in this work, the first type of mitochondrial-targeting oxime-ester photogenerator (T-Oximer) was constructed to boost type-I ROS/aryl free radicals which could induce DNA damage by DNA cleaving and facilitate high-efficiency pyroptosis-mediated photoimmunotherapy. Detailed mechanism investigations revealed that T-Oximer could produce aryl free radicals via photolysis reaction and generate type-I ROS (O₂^•− and •OH) based on the type-I electron transfer process. Meanwhile, T-Oximer could accumulate in the mitochondria, boost mitochondrial radicals, and damage mitochondria in hypoxic tumor cells. Of peculiar interest, T-Oixmer could bind with DNA and cleave DNA to induce DNA damage. Combined mitochondrial damage with DNA cleavage, T-Oximer can initiate pyroptosis, activate the ICD effect, and trigger robust systemic antitumor immunity for efficient tumor regression and metastasis suppression. Our finding provides a new strategy for constructing oxygen-independent photogenerator for high-efficiency pyroptosis-mediated anti-hypoxia photoimmunotherapy.