平衡
癌症
免疫疗法
癌症研究
癌症免疫疗法
生物
医学
免疫学
细胞生物学
遗传学
作者
H. Li,Yishuang Sun,Yao Yuxia,Shanwen Ke,Nannan Zhang,Wenjun Xiong,Jie Shi,Chuan He,Xiangling Xiao,Haisheng Yu,Panpan Dai,Bolin Xiang,Xiaoming Xing,Guo Xu,Wenjing Song,Jukun Song,Jinfang Zhang
标识
DOI:10.1073/pnas.2315541121
摘要
Ferroptosis is an iron-dependent type of regulated cell death resulting from extensive lipid peroxidation and plays a critical role in various physiological and pathological processes. However, the regulatory mechanisms for ferroptosis sensitivity remain incompletely understood. Here, we report that homozygous deletion of Usp8 (ubiquitin-specific protease 8) in intestinal epithelial cells (IECs) leads to architectural changes in the colonic epithelium and shortens mouse lifespan accompanied by increased IEC death and signs of lipid peroxidation. However, mice with heterozygous deletion of Usp8 in IECs display normal phenotype and become resistant to azoxymethane/dextran sodium sulfate-induced colorectal tumorigenesis. Mechanistically, USP8 interacts with and deubiquitinates glutathione peroxidase 4 (GPX4), leading to GPX4 stabilization. Thus, USP8 inhibition destabilizes GPX4 and sensitizes cancer cells to ferroptosis in vitro. Notably, USP8 inhibition in combination with ferroptosis inducers retards tumor growth and enhances CD8+ T cell infiltration, which potentiates tumor response to anti-PD-1 immunotherapy in vivo. These findings uncover that USP8 counteracts ferroptosis by stabilizing GPX4 and highlight targeting USP8 as a potential therapeutic strategy to boost ferroptosis for enhancing cancer immunotherapy.
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