Immune-mediated antitumor effect by type 2 diabetes drug, metformin

Proc Natl Acad Sci U S A. 2015 Feb 10;112(6):1809-14. doi: 10.1073/pnas.1417636112. Epub 2015 Jan 26.


Metformin, a prescribed drug for type 2 diabetes, has been reported to have anti-cancer effects; however, the underlying mechanism is poorly understood. Here we show that this mechanism may be immune-mediated. Metformin enabled normal but not T-cell-deficient SCID mice to reject solid tumors. In addition, it increased the number of CD8(+) tumor-infiltrating lymphocytes (TILs) and protected them from apoptosis and exhaustion characterized by decreased production of IL-2, TNFα, and IFNγ. CD8(+) TILs capable of producing multiple cytokines were mainly PD-1(-)Tim-3(+), an effector memory subset responsible for tumor rejection. Combined use of metformin and cancer vaccine improved CD8(+) TIL multifunctionality. The adoptive transfer of antigen-specific CD8(+) T cells treated with metformin concentrations as low as 10 μM showed efficient migration into tumors while maintaining multifunctionality in a manner sensitive to the AMP-activated protein kinase (AMPK) inhibitor compound C. Therefore, a direct effect of metformin on CD8(+) T cells is critical for protection against the inevitable functional exhaustion in the tumor microenvironment.

Keywords: CD8T cells; antitumor immunity; immune exhaustion; multifunctionality; tumor microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / antagonists & inhibitors
  • Adoptive Transfer
  • Animals
  • Antineoplastic Agents / immunology
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Apoptosis / immunology
  • CD8-Positive T-Lymphocytes / drug effects*
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / transplantation
  • Cell Movement / immunology
  • Cytokines / immunology
  • Lymphocytes, Tumor-Infiltrating / drug effects*
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / transplantation
  • Metformin / immunology
  • Metformin / pharmacology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, SCID
  • Neoplasms / drug therapy*
  • Tumor Microenvironment / immunology*


  • Antineoplastic Agents
  • Cytokines
  • Metformin
  • AMP-Activated Protein Kinases