Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, The Third Affiliated Hospital, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China.
Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China.
Nat Rev Clin Oncol. 2021 May;18(5):280-296. doi: 10.1038/s41571-020-00462-0. Epub 2021 Jan 29.
The discovery of regulated cell death processes has enabled advances in cancer treatment. In the past decade, ferroptosis, an iron-dependent form of regulated cell death driven by excessive lipid peroxidation, has been implicated in the development and therapeutic responses of various types of tumours. Experimental reagents (such as erastin and RSL3), approved drugs (for example, sorafenib, sulfasalazine, statins and artemisinin), ionizing radiation and cytokines (such as IFNγ and TGFβ1) can induce ferroptosis and suppress tumour growth. However, ferroptotic damage can trigger inflammation-associated immunosuppression in the tumour microenvironment, thus favouring tumour growth. The extent to which ferroptosis affects tumour biology is unclear, although several studies have found important correlations between mutations in cancer-relevant genes (for example, RAS and TP53), in genes encoding proteins involved in stress response pathways (such as NFE2L2 signalling, autophagy and hypoxia) and the epithelial-to-mesenchymal transition, and responses to treatments that activate ferroptosis. Herein, we present the key molecular mechanisms of ferroptosis, describe the crosstalk between ferroptosis and tumour-associated signalling pathways, and discuss the potential applications of ferroptosis in the context of systemic therapy, radiotherapy and immunotherapy.
调控细胞死亡过程的发现促进了癌症治疗的进展。在过去的十年中，铁依赖性的细胞死亡形式——脂质过氧化驱动的铁死亡，与各种类型肿瘤的发生和治疗反应有关。实验试剂（如 erastin 和 RSL3）、批准的药物（如索拉非尼、柳氮磺胺吡啶、他汀类药物和青蒿素）、电离辐射和细胞因子（如 IFNγ 和 TGFβ1）可诱导铁死亡并抑制肿瘤生长。然而，铁死亡损伤可在肿瘤微环境中引发炎症相关的免疫抑制，从而有利于肿瘤生长。铁死亡对肿瘤生物学的影响程度尚不清楚，尽管有几项研究发现了与癌症相关基因（如 RAS 和 TP53）、参与应激反应途径的基因（如 NFE2L2 信号、自噬和缺氧）以及上皮-间充质转化的突变之间存在重要相关性，以及与激活铁死亡的治疗反应之间存在相关性。本文中，我们介绍了铁死亡的关键分子机制，描述了铁死亡与肿瘤相关信号通路之间的串扰，并讨论了铁死亡在全身治疗、放疗和免疫治疗中的潜在应用。
