Cell Death Investigation and Therapy Lab, Department of Human Structure and Repair, Ghent University, Ghent, Belgium.
Cancer Research Institute Ghent, Ghent, Belgium.
J Immunother Cancer. 2021 Dec;9(12). doi: 10.1136/jitc-2021-003430.
Ferroptosis is a recently discovered form of regulated cell death that is morphologically, genetically, and biochemically distinct from apoptosis and necroptosis, and its potential use in anticancer therapy is emerging. The strong immunogenicity of (early) ferroptotic cancer cells broadens the current concept of immunogenic cell death and opens up new possibilities for cancer treatment. In particular, induction of immunogenic ferroptosis could be beneficial for patients with cancers resistant to apoptosis and necroptosis. However, ferroptotic cancer cells may be a rich source of oxidized lipids, which contribute to decreased phagocytosis and antigen cross-presentation by dendritic cells and thus may favor tumor evasion. This could explain the non-immunogenicity of late ferroptotic cells. Besides the presence of lactate in the tumor microenvironment, acidification and hypoxia are essential factors promoting ferroptosis resistance and affecting its immunogenicity. Here, we critically discuss the crucial mediators controlling the immunogenicity of ferroptosis that modulate the induction of antitumor immunity. We emphasize that it will be necessary to also identify the tolerogenic (ie, immunosuppressive) nature of ferroptosis, which can lead to tumor evasion.
铁死亡是一种新近发现的细胞程序性死亡方式，其在形态学、遗传学和生物化学上有别于细胞凋亡和细胞坏死，其在癌症治疗中的潜在应用正在出现。（早期）铁死亡癌细胞的强免疫原性拓宽了当前免疫原性细胞死亡的概念，并为癌症治疗开辟了新的可能性。特别是，诱导免疫原性铁死亡可能对那些对细胞凋亡和细胞坏死有抵抗性的癌症患者有益。然而，铁死亡癌细胞可能是氧化脂质的丰富来源，这有助于降低树突状细胞的吞噬作用和抗原交叉呈递，从而可能有利于肿瘤逃避。这可以解释晚期铁死亡细胞的非免疫原性。除了肿瘤微环境中存在乳酸外，酸化和缺氧也是促进铁死亡抵抗和影响其免疫原性的关键因素。在这里，我们批判性地讨论了控制铁死亡免疫原性的关键介质，这些介质调节抗肿瘤免疫的诱导。我们强调，有必要确定铁死亡的耐受原性（即免疫抑制性）本质，这可能导致肿瘤逃避。
