Molecular Engineering Boosts Photon-Activated Immunotherapy for Prostate Cancer Through Concurrent Pyroptosis and cGAS-STING Pathway Activation.

Prostate cancer therapy is often limited by metastasis, drug resistance, and systemic toxicity. Photodynamic immunotherapy (PDIT) offers a promising alternative, yet its efficacy depends on photosensitizers that can simultaneously generate reactive oxygen species (ROS) and activate antitumor immunity. Herein, three thiophene (T) dyes based on triphenylamine (D) and N-ethyl-benzoselenazolium iodide (Se) (DTSe)-based photosensitizers were molecularly engineered by modulating the π-conjugated structure. Incorporation of a carbazole unit affords DZTSe with suppressed fluorescence, enlarged Huang-Rhys factor, reduced singlet-triplet energy gap, and prolonged triplet-state lifetime, resulting in enhanced ROS generation. Notably, DZTSe exhibits multi-organelle localization in the endoplasmic reticulum and mitochondria, concurrently inducing pyroptosis and activating the cGAS-STING pathway. This dual stress-immune activation reprograms the tumor microenvironment and enables effective eradication of primary tumors and suppression of distant lesions in vivo, providing a molecular blueprint for immune-activating photosensitizers.