Extracellular 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.


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The RNA-seq raw datasets generated during this study are deposited to NCBI GEO database with the accession number GSE216623 and GSE219257. The CUT&Tagseq datasets are available at GEO (accession number GSE216623). Metabolomics data have been deposited to the EMBL-EBI MetaboLights database with the identifier MTBLS6661 (https://www.ebi.ac.uk/metabolights/MTBLS6661). Any additional materials and reagents are available from the corresponding author upon reasonable request. Source data are provided with this paper.
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