文章：

年龄相关的烟酰胺腺嘌呤二核苷酸下降驱动CAR-T细胞衰竭

Age-associated nicotinamide adenine dinucleotide decline drives CAR-T cell failure 

原文发布日期：2025-05-20 

英文摘要：

Chimeric antigen receptor (CAR) T cell therapy is one of the most promising cancer treatments. However, different hurdles are limiting its application and efficacy. In this context, how aging influences CAR-T cell outcomes is largely unknown. Here we show that CAR-T cells generated from aged female mice present a mitochondrial dysfunction derived from nicotinamide adenine dinucleotide (NAD) depletion that leads to poor stem-like properties and limited functionality in vivo. Moreover, human data analysis revealed that both age and NAD metabolism determine the responsiveness to CAR-T cell therapy. Targeting NAD pathways, we were able to recover the mitochondrial fitness and functionality of CAR-T cells derived from older adults. Altogether, our study demonstrates that aging is a limiting factor to successful CAR-T cell responses. Repairing metabolic and functional obstacles derived from age, such as NAD decline, is a promising strategy to improve current and future CAR-T cell therapies. 

摘要翻译：

杂交抗原受体T细胞（Chimeric antigen receptor, CAR）疗法是治疗癌症最具前景的方法之一。然而，尽管存在诸多障碍，其在临床应用和疗效上仍有限制。在此背景下，年龄对CAR-T细胞效果的影响尚不明确。本研究发现，来自年老的小鼠的CAR-T细胞出现线粒体功能异常，这种异常来源于尼古丁酸单核苷酸(Nicotinamide adenine dinucleotide, NAD)减少，导致 stem-like 特性差、体内功能受限。同时，通过人类数据分析发现，年龄和NAD代谢共同决定受对CAR-T细胞疗法的应答效果。靶向NAD通路，他们成功修复了年老患者的CAR-T细胞线粒体健康和功能。综上所述，本研究证明年龄是影响 CAR-T 细胞成功响应的关键限制因素之一。通过修复由年龄引起的代谢和功能障碍（如 NAD 缺乏），是一个有潜力提高目前及未来 CAR-T 疗法效果的策略。 

原文链接：

https://www.nature.com/articles/s43018-025-00982-7