复旦大学骆菲菲课题组近日取得一项新成果。经过不懈努力，他们揭示了Foxp3通过代谢重编程赋予嵌合抗原受体T细胞长期疗效。这一研究成果发表在2025年5月5日出版的国际学术期刊《细胞—代谢》上。

利用这一特性，课题组人员通过与第三代CAR构建体共表达Foxp3来生成CAR-TFoxp3细胞。CAR-TFoxp3细胞表现出明显的代谢重编程，其标志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与动力蛋白相关蛋白1的相互作用驱动的。至关重要的是，CAR-TFoxp3细胞没有获得调节性T细胞免疫抑制功能，而是通过Foxp3介导的适应表现出增强的抗肿瘤效力和减少呼气标志物的表达。在人源化免疫系统模型中证实了其有效的抗肿瘤作用和无免疫抑制作用。他们的发现建立了一种基于代谢重编程的策略，以增强CAR-T细胞在敌对肿瘤微环境中的适应性，同时保持治疗效果。

据介绍，肿瘤微环境以低氧张力和缺乏营养物质为特征，损害了嵌合抗原受体(CAR)T细胞的代谢，导致T细胞衰竭和功能障碍。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。

附：英文原文

Title: Foxp3 confers long-term efficacy of chimeric antigen receptor-T cells via metabolic reprogramming

Author: Congyi Niu, Huan Wei, Xuanxuan Pan, Yuedi Wang, Huan Song, Congwen Li, Jingbo Qie, Jiawen Qian, Shaocong Mo, Wanwei Zheng, Kameina Zhuma, Zixin Lv, Yiyuan Gao, Dan Zhang, Hui Yang, Ronghua Liu, Luman Wang, Wenwei Tu, Jie Liu, Yiwei Chu, Feifei Luo

Issue&Volume: 2025-05-05

Abstract: 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-TFoxp3 cells by co-expressing Foxp3 with a third-generation CAR construct. The CAR-TFoxp3 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-TFoxp3 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.

DOI: 10.1016/j.cmet.2025.04.008

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(25)00218-9