Molecular Engineering of Curcumin-Based Lysosome-Targeting Photosensitizers for Boosting Tumor Photoimmunotherapy via Ferroptosis/Pyroptosis Activation and Autophagy Inhibition.

Abstract

Developing novel therapeutics that can induce nonapoptotic tumor cell death pathways is considered a powerful strategy for antitumor immune activation. Photodynamic therapy (PDT) presents a noninvasive modality with the ability to motivate immunogenic cell death (ICD), but is commonly subject to the hypoxic tumor microenvironment and impeded by protective cellular autophagy, which severely limits its immune effects and therapeutic outcomes. Herein, we develop a curcumin-derived photosensitizer (Cur-T) through a twisted-planar molecular engineering strategy for increasing photon absorption and modulating triplet excited-state energy to enhance ROS (especially type I) generation. Cur-T is endowed with NIR emission, typical aggregation-induced emission (AIE) properties, high type I/II ROS generation capacity, and potent photocytotoxicity under both normoxic and hypoxic conditions. Notably, Cur-T specifically targets and destroys lysosomes, which impairs protective cellular autophagy and triggers immune-activating cell death pathways, including ferroptosis and caspase-3/GSDME-dependent pyroptosis. <i>In vivo</i> study verifies the excellent antitumor immune activation performances of Cur-T-mediated PDT, which significantly suppresses both primary and distant tumors and inhibits tumor lung metastasis. Overall, this work provides useful guidance for the rational design of natural product-derived high-performance photosensitizers and highlights the advantages of applying photoimmunotherapy with ICD activation and cytoprotective autophagy inhibition for tumor treatments.