Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China.
Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China.
Cell Death Dis. 2022 Nov 5;13(11):925. doi: 10.1038/s41419-022-05384-6.
The term ferroptosis was put forward in 2012 and has been researched exponentially over the past few years. Ferroptosis is an unconventional pattern of iron-dependent programmed cell death, which belongs to a type of necrosis and is distinguished from apoptosis and autophagy. Actuated by iron-dependent phospholipid peroxidation, ferroptosis is modulated by various cellular metabolic and signaling pathways, including amino acid, lipid, iron, and mitochondrial metabolism. Notably, ferroptosis is associated with numerous diseases and plays a double-edged sword role. Particularly, metastasis-prone or highly-mutated tumor cells are sensitive to ferroptosis. Hence, inducing or prohibiting ferroptosis in tumor cells has vastly promising potential in treating drug-resistant cancers. Immunotolerant cancer cells are not sensitive to the traditional cell death pathway such as apoptosis and necroptosis, while ferroptosis plays a crucial role in mediating tumor and immune cells to antagonize immune tolerance, which has broad prospects in the clinical setting. Herein, we summarized the mechanisms and delineated the regulatory network of ferroptosis, emphasized its dual role in mediating immune tolerance, proposed its significant clinical benefits in the tumor immune microenvironment, and ultimately presented some provocative doubts. This review aims to provide practical guidelines and research directions for the clinical practice of ferroptosis in treating immune-resistant tumors.
铁死亡这一概念于 2012 年被提出，在过去几年中得到了迅猛发展。铁死亡是一种铁依赖性的非凋亡性细胞程序性死亡方式，属于细胞坏死的一种类型，与细胞凋亡和自噬不同。铁死亡受铁依赖性的磷脂过氧化作用所调控，受多种细胞代谢和信号通路的调节，包括氨基酸、脂质、铁和线粒体代谢。值得注意的是，铁死亡与许多疾病有关，具有双重作用。特别是易转移或高度突变的肿瘤细胞对铁死亡敏感。因此，在治疗耐药性癌症方面，诱导或抑制肿瘤细胞中的铁死亡具有广阔的应用前景。免疫耐受的肿瘤细胞对传统的细胞死亡途径（如细胞凋亡和坏死性凋亡）不敏感，而铁死亡在介导肿瘤细胞和免疫细胞拮抗免疫耐受方面发挥着关键作用，在临床应用中有广阔的前景。在此，我们总结了铁死亡的机制和调控网络，强调了其在介导免疫耐受中的双重作用，提出了其在肿瘤免疫微环境中的重要临床意义，并最终提出了一些有启发性的疑问。本综述旨在为铁死亡在治疗免疫耐药性肿瘤的临床实践中提供实用的指导和研究方向。
