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铁死亡是不同于凋亡、焦亡、坏死、自噬的细胞程序性死亡方式，其过程依赖于铁离子，其本质为谷胱甘肽过氧化物酶GPX4活性下降、脂质过氧化物和氧自由基过量积累，导致细胞膜脂质过氧化损伤，具有抑制肿瘤耐药和增强抗肿瘤免疫的特点，能够为肿瘤治疗提供新靶点、克服肿瘤耐药。自从2012年美国《细胞》正刊首次提出铁死亡以来，破译调节铁死亡的代谢途径、诱导癌细胞铁死亡逐渐成为肿瘤治疗的新策略。不过，对于雌激素受体、孕激素受体、人类表皮生长因子受体HER2均为阴性的三阴性乳腺癌，其不同亚型的铁死亡特征尚不明确。 2022年10月17日，美国《细胞》旗下《细胞代谢》在线发表复旦大学附属肿瘤医院杨帆、肖毅、丁佳涵、金希、马丁、李大强、王义平、江一舟、邵志敏等学者的研究报告，首次根据复旦分型全面解析三阴性乳腺癌的铁死亡特征，发现管腔雄激素受体亚型对铁死亡最敏感，提出针对铁死亡关键靶点GPX4联合免疫治疗的潜在治疗策略。 该研究首先整合复旦大学附属肿瘤医院大样本三阴性乳腺癌队列465例患者的多组学数据，绘制出三阴性乳腺癌铁死亡图谱，发现三阴性乳腺癌不同复旦分型的铁死亡相关代谢物和代谢途径表现型显著不同。其中，雄激素受体对于调节三阴性乳腺癌铁死亡可发挥双重作用，管腔雄激素受体亚型的特征为氧化磷脂酰乙醇胺和谷胱甘肽代谢（尤其GPX4）显著增加，这使GPX4抑制剂能够诱导铁死亡。 
随后，该研究通过动物实验证实GPX4抑制剂不仅可以诱导肿瘤铁死亡，还可以增强免疫检查点细胞程序性死亡受体PD-1抑制剂的抗肿瘤免疫作用。GPX4抑制剂联合PD-1抑制剂与单药治疗相比，治疗效果显著提高。 最后，该研究通过临床数据证实GPX4高表达且细胞溶解评分较低的三阴性乳腺癌患者对免疫治疗效果显著较差，为进一步开展临床研究奠定了基础。 因此，该研究选择新颖的切入角度，在充分挖掘数据的基础上，深入开展机制分析，首次全面破译了三阴性乳腺癌不同复旦分型的的铁死亡特征，并且最终回归临床，聚焦三阴性乳腺癌复旦分型临床治疗的难点之一，揭示了针对难治性管腔雄激素受体三阴性乳腺癌的创新免疫治疗组合策略，为三阴性乳腺癌精准免疫治疗提供了新策略。Cell Metab. 2022 Oct 17. IF: 31.373Ferroptosis heterogeneity in triple-negative breast cancer reveals an innovative immunotherapy combination strategy.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.Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China; Institutes of Biomedical Sciences, Fudan University, Shanghai, China; Chinese National Human Genome Center at Shanghai (CHGC) and Shanghai Institute for Biomedical and Pharmaceutical Technologies (SIBPT), Shanghai, China.- Integrated analysis systematically demonstrates the ferroptosis heterogeneity in TNBC
- LAR subtype of TNBC is hypersensitive to ferroptosis inducers, especially GPX4 inhibitors
- AR plays a dual role in regulating ferroptosis of LAR tumors
- Combination of GPX4 inhibitors and immunotherapy is an option for LAR tumors
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.KEYWORDS: triple-negative breast cancer, ferroptosis, heterogeneity, fatty acid metabolism, immunotherapy, treatmentDOI: 10.1016/j.cmet.2022.09.021
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