Metabolic profiling of CAR T-cells in patients reveals a shift toward amino acid-supported OXPHOS and informs transporter engineering.

Authors

Naomi Taylor, Josquin Moraly, Taisuke Kondo, King Chan, Sooraj Achar, Makoto Ando, Marie Pouzolles, Bonnie Yates, Alexandra Dreyzin, Mehdi Benzaoui, Alka Dwivedi, Saliha Majdoul, Justin Mirazee, Jaehyun Suh, Angela Su, Cedric Mongellaz, Hannah Dada, Swapna Vidhur Dautalabad, Krithikha Bhuvaneshwar, Mina O Seedhom, Valerie Zimmermann, Sandrina Kinet, Daniel Crooks, Hannah Song, Jonathan Yewdell, Christopher Chien, Olivier Hermine, Valerie Dardhalon, Steven Highfill, Thorkell Andresson, Grégoire Altan-Bonnet, Nirali Shah

Published in

Research square. Sep 15, 2026. Epub Sep 15, 2026.

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.

PMID:
42780275
Bibliographic data and abstract were imported from PubMed on 24 Sep 2026.

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