肿瘤微环境中代谢性酸性废物的积累会抑制浸润肿瘤淋巴细胞（TILs）的效应功能。然而，目前仍不清楚酸性环境如何影响T细胞代谢和分化。在这里，我们展示长时间暴露于酸性环境会重新编程T细胞的细胞内代谢和线粒体适应性，并保留T细胞的干细胞特性。机制上，高水平的细胞外酸化通过下调SLC7A5来影响蛋氨酸的摄取和代谢，进而改变关键T细胞干细胞基因启动子上H3K27me3的沉积，促进“干细胞记忆”状态的维持，并提高小鼠体内长期存活和抗肿瘤功效。我们的发现不仅揭示了细胞外酸化维持T细胞干细胞特性的意想不到的能力，而且也推进了我们对蛋氨酸代谢如何影响T细胞干细胞特性的认识。©2023.作者。

The accumulation of acidic metabolic waste products within the tumor microenvironment inhibits effector functions of tumor-infiltrating lymphocytes (TILs). However, it remains unclear how an acidic environment affects T cell metabolism and differentiation. Here we show that prolonged exposure to acid reprograms T cell intracellular metabolism and mitochondrial fitness and preserves T cell stemness. Mechanistically, elevated extracellular acidosis impairs methionine uptake and metabolism via downregulation of SLC7A5, therefore altering H3K27me3 deposition at the promoters of key T cell stemness genes. These changes promote the maintenance of a 'stem-like memory' state and improve long-term in vivo persistence and anti-tumor efficacy in mice. Our findings not only reveal an unexpected capacity of extracellular acidosis to maintain the stem-like properties of T cells, but also advance our understanding of how methionine metabolism affects T cell stemness.© 2023. The Author(s).