Liang Yuan, Zhao Yixin, Qi Zhaoyang, Li Xinru, Zhao Yuguang
Cancer Center, the First Hospital of Jilin University, Changchun, Jilin, China.
Cell Death Discov. 2025 Apr 1;11(1):128. doi: 10.1038/s41420-025-02415-x.
Ferroptosis represents an emerging, iron-dependent form of cell death driven by lipid peroxidation. In recent years, it has garnered significant attention in the realm of cancer immunotherapy, particularly in studies involving immune checkpoint inhibitors. This form of cell death not only enhances our comprehension of the tumor microenvironment but is also considered a promising therapeutic strategy to address tumor resistance, investigate immune activation mechanisms, and facilitate the development of cancer vaccines. The combination of immunotherapy with ferroptosis provides innovative targets and fresh perspectives for advancing cancer treatment. Nevertheless, tumor cells appear to possess a wider array of ferroptosis evasion strategies compared to CD8T cells, which have been conclusively shown to be more vulnerable to ferroptosis. Furthermore, ferroptosis in the TME can create a favorable environment for tumor survival and invasion. Under this premise, both inducing tumor cell ferroptosis and inhibiting T cell ferroptosis will impact antitumor immunity to some extent, and even make the final result run counter to our therapeutic purpose. This paper systematically elucidates the dual-edged sword role of ferroptosis in the antitumor process of T cells, briefly outlining the complexity of ferroptosis within the TME. It explores potential side effects associated with ferroptosis-inducing therapies and critically considers the combined application of ferroptosis-based therapies with ICIs. Furthermore, it highlights the current challenges faced by this combined therapeutic approach and points out future directions for development.
铁死亡是一种新出现的、由铁依赖性脂质过氧化驱动的细胞死亡形式。近年来，它在癌症免疫治疗领域引起了广泛关注，尤其是在涉及免疫检查点抑制剂的研究中。这种细胞死亡形式不仅增进了我们对肿瘤微环境的理解，还被认为是一种有前景的治疗策略，可用于解决肿瘤耐药性、研究免疫激活机制以及促进癌症疫苗的开发。免疫治疗与铁死亡的联合为推进癌症治疗提供了创新靶点和新视角。然而，与已被确凿证明更容易受到铁死亡影响的CD8T细胞相比，肿瘤细胞似乎拥有更多种类的铁死亡逃避策略。此外，肿瘤微环境中的铁死亡可为肿瘤存活和侵袭创造有利环境。在此前提下，诱导肿瘤细胞铁死亡和抑制T细胞铁死亡都会在一定程度上影响抗肿瘤免疫，甚至使最终结果与我们的治疗目的背道而驰。本文系统阐述了铁死亡在T细胞抗肿瘤过程中的双刃剑作用，简要概述了肿瘤微环境中铁死亡的复杂性。它探讨了诱导铁死亡疗法的潜在副作用，并批判性地考虑了基于铁死亡的疗法与免疫检查点抑制剂的联合应用。此外，它突出了这种联合治疗方法目前面临的挑战，并指出了未来的发展方向。
