美国北卡罗来纳大学Jessica E. Thaxton课题组发现，乙酰-CoA羧化酶阻碍CD8⁺ T细胞在肿瘤微环境中利用脂质。该项研究成果于2024年3月14日在线发表在《细胞—代谢》杂志上。

研究人员表示，实体瘤微环境（TME）会使肿瘤浸润T细胞（TIL）的代谢状态受损，其特点是无法维持有效的能量合成以发挥抗肿瘤功能并维持存活。TME中的T细胞必须通过线粒体脂肪酸氧化（FAO）分解脂质，以在营养压力下提供能量，而且已经证实富含FAO的T细胞善于控制癌症。然而，内源性TIL和未经修饰的细胞治疗产品无法维持肿瘤中的生物能。

研究人员发现，实体TME强加了乙酰辅酶 A（CoA）羧化酶（ACC）的永久活性，导致TIL中的脂质生物生成和储存与FAO相反。利用代谢、脂质组学和共聚焦成像策略，研究人员发现限制ACC重新改写了T细胞的新陈代谢，从而在TME压力下维持能量。限制ACC的活性会增强表明T细胞长寿的基因和表型程序，使T细胞具有更高的存活率和多功能性，从而维持对癌症的控制。

附：英文原文

Title: Acetyl-CoA carboxylase obstructs CD8+ T cell lipid utilization in the tumor microenvironment

Author: Elizabeth G. Hunt, Katie E. Hurst, Brian P. Riesenberg, Andrew S. Kennedy, Evelyn J. Gandy, Alex M. Andrews, Coral del Mar Alicea Pauneto, Lauren E. Ball, Emily D. Wallace, Peng Gao, Jeremy Meier, John J. Serody, Michael F. Coleman, Jessica E. Thaxton

Issue&Volume: 2024-03-14

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.

DOI: 10.1016/j.cmet.2024.02.009

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(24)00055-X