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

Abstract

ABSTRACT 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.