肿瘤微环境
生物化学
生物能学
化学
脂质代谢
癌细胞
β氧化
生物
细胞生物学
新陈代谢
线粒体
癌症
癌症研究
肿瘤细胞
遗传学
作者
Elizabeth G. Hunt,Katie E. Hurst,Brian Riesenberg,Andrew S. Kennedy,Evelyn J. Gandy,Alex M. Andrews,Coral del Mar Alicea Pauneto,Lauren E. Ball,E. Diane Wallace,Peng Gao,Jeremy A. Meier,John J. Serody,Michael F. Coleman,Jessica E. Thaxton
标识
DOI:10.1016/j.cmet.2024.02.009
摘要
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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