小柯机器人

复旦大学Zhi-Ming Shao，Yi-Zhou Jiang和Yi Xiao共同合作近期取得重要工作进展，他们报道三阴性乳腺癌铁死亡代谢途径的异质性揭示一种创新性联合免疫治疗策略。该项研究成果2022年10月17日在线发表于《细胞—代谢》杂志上。

研究人员整合了TNBC患者（n=465）的多组学数据，绘制了铁死亡相关代谢图谱。他们发现TNBC在与铁蛋白相关的代谢物和代谢途径方面具有异质性的表型。TNBC腔内雄性激素受体（LAR）亚型的特点是氧化磷脂酰乙醇胺和谷胱甘肽代谢（尤其是GPX4）的上调，这使得GPX4抑制剂能用来诱导铁死亡。

此外，研究人员还证实了抑制GPX4不仅可以诱导肿瘤铁死亡，还可以增强抗肿瘤免疫。GPX4抑制剂与抗PD1联合治疗效果优于单一治疗。在临床上，较高的GPX4表达与免疫治疗群体中较低的细胞溶解分数和较差的预后相关。总的来说，该研究展示了TNBC相关的铁死亡概况，揭示了难治性LAR肿瘤的一种创新性联合免疫治疗策略。

据介绍，三阴性乳腺癌（TNBC）的治疗仍然具有挑战性。破译调节铁死亡的代谢途径将为TNBC治疗策略提供新的见解。

附：英文原文

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

Author: Fan Yang, Yi Xiao, Jia-Han Ding, Xi Jin, Ding Ma, Da-Qiang Li, Jin-Xiu Shi, Wei Huang, Yi-Ping Wang, Yi-Zhou Jiang, Zhi-Ming Shao

Issue&Volume: 202210-17

Abstract: 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.

DOI: 10.1016/j.cmet.2022.09.021

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(22)00411-9

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