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

The multifunctional ability of CTLs is downregulated by interaction between immune-checkpoint molecules expressed on CTLs and their ligands expressed on cancer cells, referred to as immune exhaustion. The antibody-mediated, immune-checkpoint blockade turned out to a promising method for immunotherapy against advanced melanoma. Metformin, a drug prescribed for patients with type 2 diabetes, has been recognized to have anti-cancer effect. We found that CD8⁺ tumor infiltrating lymphocytes (TILs) is a target of metformin. CD8⁺ TILs inevitably undergo immune exhaustion, characterized by diminished production of multiple cytokines such as IL-2, TNFα, and IFNγ, followed by elimination with apoptosis. Metformin is able to counter the state. Along with conventional therapy, treatment of cancer patients with metformin may have a great advantage for cancer therapy.