三阴性乳腺癌
癌症研究
GPX4
免疫疗法
下调和上调
乳腺癌
癌症
生物
免疫学
医学
内科学
基因
生物化学
过氧化氢酶
氧化应激
谷胱甘肽过氧化物酶
作者
Fan Yang,Yi Xiao,Jiahan Ding,Xi Jin,Ding Ma,Da‐Qiang Li,Jianxin Shi,Wei Huang,Yiping Wang,Yi‐Zhou Jiang,Zhi‐Ming Shao
出处
期刊:Cell Metabolism
[Elsevier]
日期:2023-01-01
卷期号:35 (1): 84-100.e8
被引量:102
标识
DOI:10.1016/j.cmet.2022.09.021
摘要
Summary
Treatment of triple-negative breast cancer (TNBC) remains challenging. Deciphering the orchestration of metabolic pathways in regulating ferroptosis will provide new insights into TNBC therapeutic strategies. Here, we integrated the multiomics data of our large TNBC cohort (n = 465) to develop the ferroptosis atlas. We discovered that TNBCs had heterogeneous phenotypes in ferroptosis-related metabolites and metabolic pathways. The luminal androgen receptor (LAR) subtype of TNBC was characterized by the upregulation of oxidized phosphatidylethanolamines and glutathione metabolism (especially GPX4), which allowed the utilization of GPX4 inhibitors to induce ferroptosis. Furthermore, we verified that GPX4 inhibition not only induced tumor ferroptosis but also enhanced antitumor immunity. The combination of GPX4 inhibitors and anti-PD1 possessed greater therapeutic efficacy than monotherapy. Clinically, higher GPX4 expression correlated with lower cytolytic scores and worse prognosis in immunotherapy cohorts. Collectively, this study demonstrated the ferroptosis landscape of TNBC and revealed an innovative immunotherapy combination strategy for refractory LAR tumors.
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