Niu Congyi, Wei Huan, Pan Xuanxuan, Wang Yuedi, Song Huan, Li Congwen, Qie Jingbo, Qian Jiawen, Mo Shaocong, Zheng Wanwei, Zhuma Kameina, Lv Zixin, Gao Yiyuan, Zhang Dan, Yang Hui, Liu Ronghua, Wang Luman, Tu Wenwei, Liu Jie, Chu Yiwei, Luo Feifei
Department of Immunology, School of Basic Medical Sciences, Biotherapy Research Center and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China; Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China.
Department of Immunology, School of Basic Medical Sciences, Biotherapy Research Center and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
Cell Metab. 2025 Jun 3;37(6):1426-1441.e7. doi: 10.1016/j.cmet.2025.04.008. Epub 2025 May 5.
The tumor microenvironment, characterized by low oxygen tension and scarce nutrients, impairs chimeric antigen receptor (CAR)-T cell metabolism, leading to T cell exhaustion and dysfunction. Notably, Foxp3 confers a metabolic advantage to regulatory T cells under such restrictive conditions. Exploiting this property, we generated CAR-T cells by co-expressing Foxp3 with a third-generation CAR construct. The CAR-T cells exhibited distinct metabolic reprogramming, marked by downregulated aerobic glycolysis and oxidative phosphorylation coupled with upregulated lipid metabolism. This metabolic shift was driven by Foxp3's interaction with dynamin-related protein 1. Crucially, CAR-T cells did not acquire regulatory T cell immunosuppressive functions but instead demonstrated enhanced antitumor potency and reduced expression of exhaustion markers via Foxp3-mediated adaptation. The potent antitumor effect and absence of immunosuppression were confirmed in a humanized immune system mouse model. Our findings establish a metabolic reprogramming-based strategy to enhance CAR-T cell adaptability within the hostile tumor microenvironment while preserving therapeutic efficacy.
肿瘤微环境以低氧张力和营养物质匮乏为特征，会损害嵌合抗原受体（CAR）-T细胞的代谢，导致T细胞耗竭和功能障碍。值得注意的是，在这种限制性条件下，Foxp3赋予调节性T细胞代谢优势。利用这一特性，我们通过将Foxp3与第三代CAR构建体共表达来生成CAR-T细胞。这些CAR-T细胞表现出明显的代谢重编程，其特征是有氧糖酵解和氧化磷酸化下调，同时脂质代谢上调。这种代谢转变是由Foxp3与发动蛋白相关蛋白1的相互作用驱动的。至关重要的是，CAR-T细胞没有获得调节性T细胞的免疫抑制功能，而是通过Foxp3介导的适应性表现出增强的抗肿瘤效力和耗竭标志物表达降低。在人源化免疫系统小鼠模型中证实了其强大的抗肿瘤作用和无免疫抑制现象。我们的研究结果建立了一种基于代谢重编程的策略，以增强CAR-T细胞在恶劣肿瘤微环境中的适应性，同时保留治疗效果。
