biostudies-literatureCheng HOutstanding Youth Foundation of Jiangsu Province of ChinaNational Natural Science Foundation of China (National Science Foundation of China)314-330https://www.ebi.ac.uk/biostudies/studies/S-EPMC9970874biostudies-literatureUnknown5(2)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.Nature metabolismExtracellular acidosis restricts one-carbon metabolism and preserves T cell stemness.PMC9970874BK20211505BK202200498197287581971466Pan XLi GTao MChen LZhang LFrankiw LQiu YXie EYin HMa KDu JZhu WCheng HWang ZXu YfalseExtracellular acidosis restricts one-carbon metabolism and preserves T cell stemness.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.2023-01-01T00:00:00Z2023 Feb2025-04-26T10:19:36.043Z2025-04-06T13:17:58.042ZS-EPMC99708743671774910.1038/s42255-022-00730-6