谷氨酸驱动的代谢重编程通过在卵巢癌中通过mTOR-SREBP2介导的HMGCS1上调促进CAR-T细胞功能
Jiannan Chen1, Lianfeng Zhao2, Wenying Li2
1Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 WenYuan Road, Nanjing, 210023, China. cjn.njnu@foxmail.com.
Journal of translational medicine
|July 17, 2025
概括
这项研究表明,谷氨酸通过改善细胞功能和持久性来增强卵巢癌的仿真抗原受体T (CAR-T) 细胞疗法. 谷氨酸通过代谢重新连接来提高CAR-T细胞活性,为改善癌症治疗结果提供了一个有希望的策略.
科学领域:
- 免疫学 免疫学 免疫学
- 代谢工程是代谢工程.
- 在瘤学瘤学.
背景情况:
- 化学抗原受体T (CAR-T) 细胞疗法在癌症治疗方面表现有前途.
- 瘤微环境中的代谢限制可能会限制CAR-T细胞的疗效.
- 卵巢癌对当前的治疗策略构成了重大挑战.
研究的目的:
- 研究谷氨酸在增强抗卵巢癌CAR-T细胞功能的作用.
- 探索谷氨胺对CAR-T细胞影响的代谢机制.
- 在临床前模型中评估与谷氨胺预处理的CAR-T细胞的治疗潜力.
主要方法:
- 用MSLN-CAR-T细胞治疗的卵巢癌患者的代谢分析.
- 在体外评估谷氨酸预处理的CAR-T细胞增殖,CAR表达,瘤溶解和细胞因子的产生.
- 对mTOR-SREBP2-HMGCS1通路,膜稳定性和免疫突触形成的机制研究.
- 在体内评估抗瘤效应和谷氨胺预处理的CAR-T细胞的记忆表型.
主要成果:
- 在卵巢癌患者的MSLN-CAR-T细胞治疗中,增加的谷氨胺水平与积极反应相关.
- 谷氨酸预治疗显著改善了CAR-T细胞的增殖,CAR的表达,瘤溶解和细胞因子的产生 (TNF-α,IFN-γ).
- 谷氨酸激活了mTOR-SREBP2通路,对HMGCS1进行上调,增强了膜稳定性,并促进了免疫突触的形成.
- 在体内研究表明,优异的瘤透,持续的抗瘤活性,和保存的记忆子集与谷氨酸预处理的CAR-T细胞.
结论:
- 通过mTOR-SREBP2-HMGCS1轴的谷氨胺驱动的代谢重新连接可以提高卵巢癌中CAR-T细胞的疗效.
- 向谷氨胺代谢是克服代谢抵抗并改善CAR-T细胞治疗结果的可行策略.
- 这些发现为旨在通过代谢调节优化CAR-T细胞功能的临床策略提供了基础.
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