Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments

Cancer Cell. 2022 Feb 14;40(2):201-218.e9. doi: 10.1016/j.ccell.2022.01.001. Epub 2022 Jan 28.


The balance of programmed death-1 (PD-1)-expressing CD8+ T cells and regulatory T (Treg) cells in the tumor microenvironment (TME) determines the clinical efficacy of PD-1 blockade therapy through the competition of their reactivation. However, factors that determine this balance remain unknown. Here, we show that Treg cells gain higher PD-1 expression than effector T cells in highly glycolytic tumors, including MYC-amplified tumors and liver tumors. Under low-glucose environments via glucose consumption by tumor cells, Treg cells actively absorbed lactic acid (LA) through monocarboxylate transporter 1 (MCT1), promoting NFAT1 translocation into the nucleus, thereby enhancing the expression of PD-1, whereas PD-1 expression by effector T cells was dampened. PD-1 blockade invigorated the PD-1-expressing Treg cells, resulting in treatment failure. We propose that LA in the highly glycolytic TME is an active checkpoint for the function of Treg cells in the TME via upregulation of PD-1 expression.

Keywords: MYC; PD-1; lactic acid; liver metastasis; regulatory T cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers, Tumor
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / pathology
  • Cell Line, Tumor
  • Disease Models, Animal
  • Fluorescent Antibody Technique
  • Gene Expression Regulation, Neoplastic* / drug effects
  • Glycolysis
  • Humans
  • Immune Checkpoint Inhibitors / pharmacology
  • Immune Checkpoint Inhibitors / therapeutic use
  • Immune Checkpoint Proteins / metabolism
  • Immunophenotyping
  • Lactic Acid / metabolism*
  • Lactic Acid / pharmacology
  • Lymphocyte Activation
  • Lymphocyte Count
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / metabolism
  • Lymphocytes, Tumor-Infiltrating / pathology
  • Mice
  • Molecular Targeted Therapy
  • Prognosis
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Programmed Cell Death 1 Receptor / genetics*
  • Programmed Cell Death 1 Receptor / metabolism
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism*
  • Treatment Outcome
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / genetics*


  • Biomarkers, Tumor
  • Immune Checkpoint Inhibitors
  • Immune Checkpoint Proteins
  • Programmed Cell Death 1 Receptor
  • Lactic Acid