Gao Yaoxin, Liu Shasha, Huang Yifan, Wang Hui, Zhao Yuyu, Cui Xuyang, Peng Yajing, Li Feng, Zhang Yi
Biotherapy Center and Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
School of Life Sciences, Zhengzhou University, Zhengzhou, China.
Cancer Immunol Res. 2024 Dec 3;12(12):1691-1702. doi: 10.1158/2326-6066.CIR-24-0130.
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 IFNκ influenced the induction of ferroptosis. IFNκ could enhance the sensitivity of tumor cells to ferroptosis induced by the small molecule compound erastin and the polyunsaturated fatty acid arachidonic acid. Mechanistically, IFNκ in combination with arachidonic acid induced immunogenic tumor ferroptosis via an IFNAR/STAT1/ACSL4 axis. Moreover, CAR T cells engineered to express IFNκ showed increased antitumor efficiency against H460 cells (antigen positive) and H322 cells (antigen-negative) both in vitro and in vivo. We conclude that IFNκ is a potential cytokine that could be harnessed to enhance the antitumor function of CAR T cells by inducing tumor ferroptosis.
铁死亡是一种铁依赖性的细胞死亡形式，会影响癌症免疫。对铁死亡进行治疗性调节被认为是增强其他癌症治疗效果的一种潜在策略，包括嵌合抗原受体（CAR）T细胞疗法等免疫疗法。在本研究中，我们证明IFNκ会影响铁死亡的诱导。IFNκ可增强肿瘤细胞对小分子化合物埃拉斯汀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，IFNκ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，经基因工程改造以表达IFNκ的CAR T细胞在体外和体内对H460细胞（抗原阳性）和H322细胞（抗原阴性）均显示出增强的抗肿瘤效率。我们得出结论，IFNκ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。
