Near-infrared boron difluoride-based photosensitizers targeting endoplasmic reticulum stress for antitumor immunotherapy

Abstract

Endoplasmic reticulum (ER) stress has attracted growing attention in recent years as a potential therapeutic target for cancer treatment. Photosensitizers serve as inducers of ER stress, exerting their effects through the generation of reactive oxygen species (ROS), which can enhance immunogenic cell death (ICD). However, photodynamic therapy (PDT) is constrained by tumor hypoxia and the short half-life of ROS, which hinders the therapeutic efficacy of photosensitizers. Herein, three ER-targeting, heavy-atom-free boron difluoride-based photosensitizers capable of generating Type I ROS are successfully synthesized. Among these compounds, BFE-3 exhibits the highest electron affinity and demonstrates superior Type I ROS generation efficiency. Notably, BFE-3 is found to effectively induce ER stress and initiate the mitochondrial apoptotic cascade pathway. More importantly, BFE-3 can promote the release of damage-associated molecular patterns (DAMPs) from tumor cells under light irradiation, which efficiently induce ICD and activate antitumor immune responses. This boron difluoride-based photosensitizer, as a heavy-atom-free system, provides insights for developing Type I ROS-generating photosensitizers, while also offering a potential strategy for ER stress-mediated antitumor immunotherapy.