肿瘤细胞中活性氧(ROS)水平的失衡可导致脂质过氧化物(LPO)的积累,从而诱导铁死亡。此外,肿瘤中升高的ROS水平为开发基于ROS的癌症疗法提供了机会,包括光动力疗法(PDT)和铁细胞凋亡。然而,它们的抗癌功效因氧气水平不足和固有的细胞ROS调节机制而受到损害。在这里,一种靶向细胞膜的光敏剂,TBzT-CNQi,可以产生1O2,·OH,和O2•-通过I/II型过程诱导高水平的LPO用于有效的铁凋亡和光动力疗法。将FSP1抑制剂(iFSP1)与TBzT-CNQi一起下调FSP1的表达,降低细胞内辅酶Q10含量,诱导高水平的LPO,并激活初始肿瘤免疫原性铁死亡。体外和体内实验表明,细胞膜靶向I/II型PDT结合FSP1抑制可以引起强烈的ICD并激活免疫反应。随后促进CD8+T细胞浸润的侵袭,促进树突状细胞成熟,并减少肿瘤相关巨噬细胞的肿瘤浸润。该研究表明,靶向细胞膜的I/II型PDT和FSP1抑制的组合有望成为缺氧肿瘤的铁凋亡增强光动力免疫治疗的潜在策略。
An imbalance in reactive oxygen species (ROS) levels in tumor cells can result in the accumulation of lipid peroxide (LPO) which can induce ferroptosis. Moreover, elevated ROS levels in tumors present a chance to develop ROS-based cancer therapeutics including photodynamic therapy (PDT) and ferroptosis. However, their anticancer efficacies are compromised by insufficient oxygen levels and inherent cellular ROS regulatory mechanism. Herein, a cell membrane-targeting photosensitizer, TBzT-CNQi, which can generate 1O2, •OH, and O2 •- via type I/II process to induce a high level of LPO for potent ferroptosis and photodynamic therapy is developed. The FSP1 inhibitor (iFSP1) is incorporated with TBzT-CNQi to downregulate 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-targeting type I/II PDT combination with FSP1 inhibition can evoke 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.