CAR T 细胞被设计为分泌 IFN-κ，通过 IFNAR/STAT1/ACSL4 轴诱导肿瘤铁死亡。
CAR T cells engineered to secrete IFN-κ induce tumor ferroptosis via an IFNAR/STAT1/ACSL4 axis.
发表日期：2024 Aug 26
作者：
Yaoxin Gao, Shasha Liu, Yifan Huang, Hui Wang, Yuyu Zhao, Xuyang Cui, Yajing Peng, Feng Li, Yi Zhang
来源：
CYTOKINE & GROWTH FACTOR REVIEWS
摘要：
铁死亡是一种铁依赖性细胞死亡形式，会影响癌症免疫。铁死亡的治疗性调节被认为是增强其他癌症疗法疗效的潜在策略，包括嵌合抗原受体 (CAR) T 细胞疗法等免疫疗法。在这项研究中，我们证明 IFN-κ 影响铁死亡的诱导。 IFN-κ可增强肿瘤细胞对小分子化合物erastin和多不饱和脂肪酸花生四烯酸诱导的铁死亡的敏感性。从机制上讲，IFN-κ 与花生四烯酸联合通过 IFNAR/STAT1/ACSL4 轴诱导免疫原性肿瘤铁死亡。此外，表达 IFN-κ 的 CAR T 细胞在体外和体内均显示出针对 H460 细胞（抗原阳性）和 H322 细胞（抗原阴性）的抗肿瘤效率增加。我们的结论是，IFN-κ 是一种潜在的细胞因子，可通过诱导肿瘤铁死亡来增强 CAR T 细胞的抗肿瘤功能。
Ferroptosis is an iron-dependent form of cell death that influences cancer immunity. Therapeutic modulation of ferroptosis is considered a potential strategy to enhance the efficacy of other cancer therapies, including immunotherapies such as chimeric antigen receptor (CAR) T cell therapy. In this study, we demonstrated that IFN-κ influenced the induction of ferroptosis. IFN-κ could enhance the sensitivity of tumor cells to ferroptosis induced by the small molecule compound erastin and the polyunsaturated fatty acid arachidonic acid. Mechanistically, IFN-κ in combination with arachidonic acid induced immunogenic tumor ferroptosis via an IFNAR/STAT1/ACSL4 axis. Moreover, CAR T cells engineered to express IFN-κ showed increased antitumor efficiency against H460 cells (antigen positive) and H322 cells (antigen negative) both in vitro and in vivo. We conclude that IFN-κ is a potential cytokine that could be harnessed to enhance the antitumor function of CAR T cells by inducing tumor ferroptosis.