Zwitterionic Photosensitizer Triggers Photopyroptosis for Effective Cancer Immunotherapy

ABSTRACT Photopyroptosis, a lytic and immunogenic cell death modality triggered by photosensitizer (PS)‐generated reactive oxygen species under specific light irradiation, offers a promising strategy to overcome the inherent limitations of conventional cancer therapies. However, the precise design of PSs to induce photopyroptosis under hypoxic tumor microenvironments remains challenging. Herein, we report a zwitterionic nano‐photosensitizer (PCBMA‐TAPP) that combines mitochondrial‐targeted Type I photodynamic therapy (PDT) with enhanced tumor accumulation to potentiate pyroptosis‐driven immunotherapy. A comparative evaluation of three porphyrin‐based PSs identified tetra (4‐aminophenyl) porphyrin (TAPP) as a lead candidate with superior mitochondrial localization and enhanced generation of superoxide anions (•O 2 − ), enabling potent caspase‐3/gasdermin E‐mediated pyroptosis. Encapsulation of TAPP into redox‐responsive poly (carboxybetaine methacrylate) (PCBMA) nanogels prolongs circulation, enhances passive targeting, and preserves photodynamic activity. In vitro, PCBMA‐TAPP rapidly induces plasma membrane disruption, release of lactate dehydrogenase and adenosine triphosphate, and activation of the NLRP3 inflammasome, thereby promoting dendritic cell maturation. In EMT6 tumor‐bearing mice, PCBMA‐TAPP achieves 84.9% tumor growth inhibition, accompanied by elevated infiltration of CD8 + , CD4 + , and granzyme B expression, without observable systemic toxicity. These findings established a nanoplatform that synergizes organelle‐specific Type I PDT with pyroptosis‐driven immune activation, advancing a clinically translatable strategy for immunotherapy of hypoxic tumors.