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Acetyl-CoA Carboxylase Obstructs CD8+ T-Cell Lipid Utilization in the Tumor Microenvironment

ABSTRACT: The solid tumor microenvironment (TME) imprints a compromised metabolic state in tumor infiltrating T cells (TILs) hallmarked by the inability to maintain effective energy synthesis for antitumor function and survival. T cells in the TME must catabolize lipids via mitochondrial fatty acid oxidation (FAO) to supply energy in nutrient stress, and it is established that T cells enriched in FAO are adept at cancer control.However, endogenous TILs and unmodified cellular therapy products fail to sustain bioenergetics in tumors. Using patient samples and mouse models, we reveal that the solid TME imposes perpetual acetyl-CoA carboxylase (ACC) activity, invoking lipid biogenesis and storage in TILs that directly opposes FAO. Using metabolic, lipidomic, and confocal imaging strategies, we find that restricting ACC rewires T cell metabolism, enabling energy maintenance in TME stress. Moreover, limiting ACC activity potentiates a gene and phenotypic program indicative of T cell longevity, engendering T cells with increased survival and polyfunctionality, with the ability to control solid cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE254000 | GEO | 2024/03/05

REPOSITORIES: GEO

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