Ferroptosis heterogeneity in triple-negative breast cancer reveals an innovative immunotherapy combination strategy

作者：Fan Yang, Yi Xiao, Jia-Han Ding, Xi Jin, Ding Ma, Da‐Qiang Li, Jinxiu Shi, Wei Huang, Yi-Ping Wang, Yi‐Zhou Jiang, Zhi‐Ming Shao · 发表于：Cell Metabolism · 年份：2022 · DOI：10.1016/j.cmet.2022.09.021 · 被引用次数：631 · 研究领域：Ferroptosis and cancer prognosis、Cancer, Lipids, and Metabolism、RNA modifications and cancer

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.