患者CAR-T细胞的代谢谱揭示向氨基酸支持的OXPHOS转变并指导转运体工程
Metabolic profiling of CAR T-cells in patients reveals a shift toward amino acid-supported OXPHOS and informs transporter engineering
Res Sq · 2026 年 9 月 15 日 · Naomi Taylor, Josquin Moraly, Taisuke Kondo 等 32 人
CAR-T细胞（经基因改造后能识别并杀伤肿瘤的T细胞）的疗效依赖输注后的扩增和持续存在，但患者体内支持T细胞的代谢程序尚不清楚。研究者建立高通量单细胞免疫代谢分析流程，应用于儿童白血病试验，发现CAR-T输注后普遍从糖酵解转向氨基酸驱动的氧化磷酸化（OXPHOS，线粒体产生能量的方式）；依赖OXPHOS的干性样CAR-T亚群在完全缓解患者中富集。纵向血浆代谢组学显示细胞因子释放综合征期间谷氨酰胺和精氨酸等多种氨基酸被消耗，形成营养受限环境；公共数据集分析显示应答者上调氨基酸溶质载体转运体，而干扰其摄取会损害翻译、OXPHOS、干性和细胞毒性。据此筛选转运体，发现SLC1A5、SLC7A1和SLC38A9“装甲”的CAR-T氧化能力和抗白血病疗效最强，确立氨基酸转运为可靶向的代谢检查点。该研究为预印本，尚未经同行评审。
为什么推荐给您：首次在患者中系统刻画CAR-T输注后氨基酸驱动OXPHOS的代谢重塑，并据此工程改造转运体增强疗效，机制新、有转化前景，但为预印本。
不需要生物学背景，多打比方
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摘要Abstract
CAR T-cell efficacy requires post-infusion expansion and persistence, yet metabolic programs supporting T-cells in patients remain poorly defined. Here, we developed a high-throughput single-cell immunometabolic profiling pipeline and applied it across pediatric leukemia trials, revealing a conserved post-infusion CAR T-cell shift from glycolysis toward amino acid-driven oxidative phosphorylation (OXPHOS). Within this remodeling, OXPHOS-dependent stem-like CAR T-cell subsets were enriched in patients achieving complete remission. Longitudinal plasma metabolomics revealed cytokine release syndrome-associated depletion of multiple amino acids, including glutamine and arginine, during CAR T-cell expansion, creating a nutrient-restricted environment. Analysis of public CAR T-cell datasets showed that responders upregulated amino-acid solute carrier transporters, whereas disrupting uptake impaired translation, OXPHOS, stemness, and cytotoxicity. Guided by these findings, we screened amino-acid transporters for CAR T-cell engineering. SLC1A5-, SLC7A1-, and SLC38A9-armored CAR T-cells emerged as the most promising, with enhanced oxidative capacity and anti-leukemic efficacy, establishing amino acid transport as a targetable metabolic checkpoint.