STAT3 Activation-Induced Fatty Acid Oxidation in CD8+ T Effector Cells Is Critical for Obesity-Promoted Breast Tumor Growth

Cell Metab. 2020 Jan 7;31(1):148-161.e5. doi: 10.1016/j.cmet.2019.10.013. Epub 2019 Nov 21.


Although obesity is known to be critical for cancer development, how obesity negatively impacts antitumor immune responses remains largely unknown. Here, we show that increased fatty acid oxidation (FAO) driven by activated STAT3 in CD8+ T effector cells is critical for obesity-associated breast tumor progression. Ablating T cell Stat3 or treatment with an FAO inhibitor in obese mice spontaneously developing breast tumor reduces FAO, increases glycolysis and CD8+ T effector cell functions, leading to inhibition of breast tumor development. Moreover, PD-1 ligation in CD8+ T cells activates STAT3 to increase FAO, inhibiting CD8+ T effector cell glycolysis and functions. Finally, leptin enriched in mammary adipocytes and fat tissues downregulates CD8+ T cell effector functions through activating STAT3-FAO and inhibiting glycolysis. We identify a critical role of increased oxidation of fatty acids driven by leptin and PD-1 through STAT3 in inhibiting CD8+ T effector cell glycolysis and in promoting obesity-associated breast tumorigenesis.

Keywords: CD8 T cells; FAO; IFNγ; PD-1; PyMT model; STAT3; leptin; obesity; tumor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / metabolism
  • Adipose Tissue / metabolism
  • Animals
  • Breast Neoplasms / immunology*
  • Breast Neoplasms / metabolism
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism*
  • Carcinogenesis / genetics
  • Carcinogenesis / immunology*
  • Carcinogenesis / metabolism
  • Cell Line
  • Cell Proliferation / genetics
  • Chromatin Immunoprecipitation
  • Fatty Acids / metabolism*
  • Female
  • Glycolysis / genetics
  • Glycolysis / physiology
  • Humans
  • Interferon-gamma / metabolism
  • Leptin / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Obesity / immunology
  • Obesity / metabolism*
  • Oxidation-Reduction / drug effects
  • Programmed Cell Death 1 Receptor / metabolism
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*


  • Fatty Acids
  • Leptin
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Interferon-gamma