Abstract
Acetate, a precursor of acetyl-CoA, is instrumental in energy production, lipid synthesis and protein acetylation. However, whether acetate reprogrammes tumour metabolism and plays a role in tumour immune evasion remains unclear. Here, we show that acetate is the most abundant short-chain fatty acid in human non-small cell lung cancer tissues, with increased tumour-enriched acetate uptake. Acetate-derived acetyl-CoA induces c-Myc acetylation, which is mediated by the moonlighting function of the metabolic enzyme dihydrolipoamide S-acetyltransferase. Acetylated c-Myc increases its stability and subsequent transcription of the genes encoding programmed death-ligand 1, glycolytic enzymes, monocarboxylate transporter 1 and cell cycle accelerators. Dietary acetate supplementation promotes tumour growth and inhibits CD8+ T cell infiltration, whereas disruption of acetate uptake inhibits immune evasion, which increases the efficacy of anti-PD-1-based therapy. These findings highlight a critical role of acetate promoting tumour growth beyond its metabolic role as a carbon source by reprogramming tumour metabolism and immune evasion, and underscore the potential of controlling acetate metabolism to curb tumour growth and improve the response to immune checkpoint blockade therapy.
乙酸酯是乙酰-CoA的前体，在能量产生、脂质合成和蛋白质乙酰化过程中起着重要作用。然而，乙酸酯是否会重编程肿瘤代谢并在肿瘤免疫逃避中发挥作用仍不清楚。在这项研究中，我们发现乙酸酯是人类非小细胞肺癌组织中最丰富的短链脂肪酸，肿瘤富集的乙酸酯摄取量增加。乙酸衍生的乙酰-CoA可诱导c-Myc乙酰化，这种乙酰化是由代谢酶二氢脂酰胺S-乙酰转移酶的月光功能介导的。乙酰化的 c-Myc 增加了其稳定性，并随后增加了编码PD-L1、糖酵解酶、单羧酸盐转运体1和细胞周期加速因子的基因转录。膳食中补充醋酸盐会促进肿瘤生长并抑制CD8+ T细胞浸润，而破坏乙酸酯的吸收则会抑制免疫逃避，从而提高基于抗PD-1疗法的疗效。这些发现强调了乙酸酯除了作为碳源的代谢作用外，还通过重编程肿瘤代谢和免疫逃避促进肿瘤生长的关键作用，并强调了控制醋酸代谢以抑制肿瘤生长和改善对免疫检查点阻断疗法的反应的潜力。
