活性氧
肿瘤微环境
化学
GPX4
谷胱甘肽
癌症研究
刺
癌症免疫疗法
癌细胞
细胞内
脂质过氧化
免疫疗法
酶
生物化学
免疫系统
癌症
谷胱甘肽过氧化物酶
生物
免疫学
肿瘤细胞
航空航天工程
工程类
遗传学
作者
Zhenxin Wang,Peng Zhou,Yuting Li,D Zhang,Fuchao Chu,Zhiqin Chen,Bin Pan,Fenglei Gao
出处
期刊:Small
[Wiley]
日期:2023-12-10
标识
DOI:10.1002/smll.202308397
摘要
Abstract Due to the inherent low immunogenicity and immunosuppressive tumor microenvironment (TME) of malignant cancers, the clinical efficacy and application of tumor immunotherapy have been limited. Herein, a bimetallic drug‐gene co‐loading network (Cu/ZIF‐8@U‐104@siNFS1‐HA) is developed that increased the intracellular labile iron pool (LIP) and enhanced the weakly acidic TME by co‐suppressing the dual enzymatic activities of carbonic anhydrase IX (CA IX) and cysteine desulfurylase (NFS1), inducing a safe and efficient initial tumor immunogenic ferroptosis. During this process, Cu 2+ is responsively released to deplete glutathione (GSH) and reduce the enzyme activity of glutathione peroxidase 4 (GPX4), achieving the co‐inhibition of the three enzymes and further inducing lipid peroxidation (LPO). Additionally, the reactive oxygen species (ROS) storm in target cells promoted the generation of large numbers of double‐stranded DNA breaks. The presence of Zn 2+ substantially increased the expression of cGAS/STING, which cooperated with ferroptosis to strengthen the immunogenic cell death (ICD) response and remodel the immunosuppressive TME. In brief, Cu/ZIF‐8@U‐104@siNFS1‐HA linked ferroptosis with immunotherapy through multiple pathways, including the increase in LIP, regulation of pH, depletion of GSH/GPX4, and activation of STING, effectively inhibiting cancer growth and metastasis.
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