Cell Membrane-Targeting Type I/II Photodynamic Therapy Combination with FSP1 Inhibition for Ferroptosis-enhanced Photodynamic Immunotherapy.

An imbalance in reactive oxygen species (ROS) levels in tumor cells can result in the accumulation of lipid peroxide (LPO) which could induce ferroptosis. Moreover, elevated ROS levels in tumors present a chance to develop ROS-based cancer therapeutics including photodynamic therapy and ferroptosis. However, their anticancer efficacies are compromised by the insufficient oxygen levels in solid tumors and inherent cellular ROS regulatory mechanism. Herein, we develop a cell membrane-targeting photosensitizer, TBzT-CNQi, which could generate 1 O 2 , •OH, and O 2 •- via type I/II process to induce a high level of LPO for potent ferroptosis and photodynamic therapy. The FSP1 inhibitor (iFSP1) is incorporated with the cell membrane-targeting type I/II PDT based on TBzT-CNQi to down-regulate FSP1 expression, lower the intracellular CoQ10 content, induce a high level of LPO, and activate initial tumor immunogenic ferroptosis. In vitro and in vivo experiments demonstrate that the cell membrane-tergeting type I/II photodynamic therapy combination with FSP1 inhibition can evoke a strong ICD and activate the immune response, which subsequently promotes the invasion of CD8+ T cells infiltration, facilitates the dendritic cell maturation, and decreases the tumor infiltration of tumor-associated macrophages. The study indicates that the combination of cell membrane-targeting type I/II PDT and FSP1 inhibition holds promise as a potential strategy for ferroptosis-enhanced photodynamic immunotherapy of hypoxia tumors. This article is protected by copyright. All rights reserved.