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.

铁死亡这个术语于 2012 年提出，并在过去几年中得到了指数级的研究。铁死亡是铁依赖性程序性细胞死亡的一种非常规模式，属于坏死类型，与细胞凋亡和自噬不同。在铁依赖性磷脂过氧化作用的驱动下，铁死亡受到多种细胞代谢和信号传导途径的调节，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，并且发挥着双刃剑的作用。特别是，易于转移或高度突变的肿瘤细胞对铁死亡敏感。因此，诱导或抑制肿瘤细胞的铁死亡在治疗耐药癌症方面具有巨大的潜力。免疫耐受的癌细胞对细胞凋亡、坏死性凋亡等传统细胞死亡途径不敏感，而铁死亡在介导肿瘤和免疫细胞拮抗免疫耐受方面发挥着至关重要的作用，在临床上具有广阔的前景。在此，我们总结了铁死亡的机制并描绘了其调节网络，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显着临床益处，并最终提出了一些挑衅性的疑问。本综述旨在为铁死亡治疗免疫抵抗肿瘤的临床实践提供实用指南和研究方向。