Extracellular acidosis restricts one-carbon metabolism and preserves T cell stemness
Hongcheng Cheng, Yajing Qiu, Yue Xu, Li Chen, Kaili Ma, Mengyuan Tao, Luke Frankiw, Hongli Yin, Ermei Xie, Xiaoli Pan, Jing Du, Zhe Wang, Wenjie Zhu, Lu Chen, Lianjun Zhang, Guideng Li
Abstract
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.