Methionine consumption by cancer cells drives a progressive upregulation of PD-1 expression in CD4 T cells

Nat Commun. 2023 May 5;14(1):2593. doi: 10.1038/s41467-023-38316-9.


Programmed cell death protein 1 (PD-1), expressed on tumor-infiltrating T cells, is a T cell exhaustion marker. The mechanisms underlying PD-1 upregulation in CD4 T cells remain unknown. Here we develop nutrient-deprived media and a conditional knockout female mouse model to study the mechanism underlying PD-1 upregulation. Reduced methionine increases PD-1 expression on CD4 T cells. The genetic ablation of SLC43A2 in cancer cells restores methionine metabolism in CD4 T cells, increasing the intracellular levels of S-adenosylmethionine and yielding H3K79me2. Reduced H3K79me2 due to methionine deprivation downregulates AMPK, upregulates PD-1 expression and impairs antitumor immunity in CD4 T cells. Methionine supplementation restores H3K79 methylation and AMPK expression, lowering PD-1 levels. AMPK-deficient CD4 T cells exhibit increased endoplasmic reticulum stress and Xbp1s transcript levels. Our results demonstrate that AMPK is a methionine-dependent regulator of the epigenetic control of PD-1 expression in CD4 T cells, a metabolic checkpoint for CD4 T cell exhaustion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Animals
  • CD4-Positive T-Lymphocytes*
  • CD8-Positive T-Lymphocytes
  • Female
  • Methionine / metabolism
  • Mice
  • Mice, Knockout
  • Neoplasms* / metabolism
  • Programmed Cell Death 1 Receptor* / metabolism
  • Racemethionine / metabolism
  • Up-Regulation


  • AMP-Activated Protein Kinases
  • Methionine
  • Programmed Cell Death 1 Receptor
  • Racemethionine
  • Pdcd1 protein, mouse