化学
花生四烯酸
酶
活性氧
GPX4
癌症研究
生物化学
癌症免疫疗法
免疫原性细胞死亡
磷脂酶A2
细胞生物学
免疫疗法
谷胱甘肽
免疫系统
程序性细胞死亡
免疫学
生物
细胞凋亡
谷胱甘肽过氧化物酶
作者
Yang Liu,Rui Niu,Ruiping Deng,Shuyan Song,Yinghui Wang,Hongjie Zhang
摘要
Immunotherapy is currently the most promising treatment strategy for long-term tumor regression. However, current cancer immunotherapy shows low response rates due to insufficient immunogenicity of tumor cells. Herein, we report a strategy to keep tumor cells highly immunogenic by triggering cascade immunogenic tumor ferroptosis. We developed a six-enzyme co-expressed nanoplatform: lipoxygenase (LOX) and phospholipase A2 (PLA2)-co-loaded FeCo/Fe-Co dual-metal atom nanozyme (FeCo/Fe-Co DAzyme/PL), which can not only induce initial immunogenic tumor ferroptosis through its own multi-enzyme mimetic activities but also up-regulate arachidonic acid (AA) expression to synergize with CD8+ T cell-derived IFN-γ to induce ACSL4-mediated immunogenic tumor ferroptosis. During this process, FeCo/Fe-Co DAzyme/PL can induce lipid peroxidation (LPO) by efficiently generating reactive oxygen species (ROS) and depleting GSH and GPX4 at tumor sites. Additionally, free AA released from PLA2 catalysis is converted into arachidonyl-CoA under the activation of ACSL4 stimulated by IFN-γ, which is further incorporated into phospholipids on membranes and peroxidized with the participation of LOX. Consequently, FeCo/Fe-Co DAzyme/PL can promote irreversible cascade immunogenic ferroptosis through multiple ROS storms, GSH/GPX4 depletion, LOX catalysis, and IFN-γ-mediated ACSL4 activation, constructing an effective pathway to overcome the drawbacks of current immunotherapy.
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