调查铁死亡在肿瘤微环境中的作用，以找到结合疗法作为肝癌治疗的方案。被认为是铁死亡的主要调控因子的谷胱甘肽过氧化物酶4（GPx4），在小鼠模型中进行了基因改变，以分析铁死亡对肿瘤细胞和免疫肿瘤微环境的影响。研究结果为鉴定与铁死亡诱导剂相结合的其他靶点，用于HCC和肝部转移的联合治疗提供了基础。令人惊讶的是，仅在肝细胞中的GPx4丧失并没有抑制肝细胞癌的发生。相反，GPx4相关的铁死亡性肝细胞死亡引起抑制肿瘤的免疫反应，表现为CD8+ T细胞的CXCL10依赖性浸润，该反应与PD-L1和标记的HMGB1介导的髓样抑制性细胞浸润相平衡。阻断PD-1或HMGB1可以释放T细胞活化，延长具有Gpx4缺陷的肝肿瘤的小鼠的生存时间。铁死亡诱导剂天然化合物卡容素A、CXCR2抑制剂SB225002和α-PD-1的三联组合可极大地提高具有肝肿瘤的野生类型小鼠的生存率。相比之下，相同的组合对皮下生长的CRC实体细胞不影响肿瘤生长，而减少了它们在肝脏的转移生长。我们的数据突出了一种上下文特定的铁死亡诱导的免疫反应，该反应可以在原发性肝肿瘤和肝转移的治疗中得到治疗上的应用。 © 作者（或其雇主）2023年。在CC BY-NC下允许重新使用。不允许商业再利用。由BMJ出版。

Investigating the effect of ferroptosis in the tumour microenvironment to identify combinatory therapy for liver cancer treatment.Glutathione peroxidase 4 (GPx4), which is considered the master regulator of ferroptosis, was genetically altered in murine models for hepatocellular carcinoma (HCC) and colorectal cancer (CRC) to analyse the effect of ferroptosis on tumour cells and the immune tumour microenvironment. The findings served as foundation for the identification of additional targets for combine therapy with ferroptotic inducer in the treatment of HCC and liver metastasis.Surprisingly, hepatocyte-restricted GPx4 loss does not suppress hepatocellular tumourigenesis. Instead, GPx4-associated ferroptotic hepatocyte death causes a tumour suppressive immune response characterised by a CXCL10-dependent infiltration of cytotoxic CD8+ T cells that is counterbalanced by PD-L1 upregulation on tumour cells as well as by a marked HMGB1-mediated myeloid derived suppressor cell (MDSC) infiltration. Blocking PD-1 or HMGB1 unleashes T cell activation and prolongs survival of mice with Gpx4-deficient liver tumours. A triple combination of the ferroptosis inducing natural compound withaferin A, the CXCR2 inhibitor SB225002 and α-PD-1 greatly improves survival of wild-type mice with liver tumours. In contrast, the same combination does not affect tumour growth of subcutaneously grown CRC organoids, while it decreases their metastatic growth in liver.Our data highlight a context-specific ferroptosis-induced immune response that could be therapeutically exploited for the treatment of primary liver tumours and liver metastases.© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.