Acetyl-CoA carboxylase obstructs CD8+ T cell lipid utilization in the tumor microenvironment.
Cell Metab
; 36(5): 969-983.e10, 2024 May 07.
Article
em En
| MEDLINE
| ID: mdl-38490211
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. We reveal that the solid TME imposes perpetual acetyl-coenzyme A (CoA) carboxylase (ACC) activity, invoking lipid biogenesis and storage in TILs that opposes FAO. Using metabolic, lipidomic, and confocal imaging strategies, we find that restricting ACC rewires T cell metabolism, enabling energy maintenance in TME stress. Limiting ACC activity potentiates a gene and phenotypic program indicative of T cell longevity, engendering T cells with increased survival and polyfunctionality, which sustains cancer control.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Acetil-CoA Carboxilase
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Linfócitos T CD8-Positivos
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Metabolismo dos Lipídeos
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Microambiente Tumoral
Limite:
Animals
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Female
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Humans
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article