Metformin promotes antitumor activity of NK cells via overexpression of miRNA-150 and miRNA-155

Objectives: Metformin, an oral anti-diabetic drug, is known to possess a powerful antitumor effect by modulating the tumor-immune interaction. The precise influence of metformin on natural killer (NK) cells, a crucial innate immunity player, is not completely understood. In our study, analyses of the effect of metformin on the NK cell functional phenotype were performed, and the potential mechanisms underlying it were investigated. Methods: BALB/C wild type mice were treated with metformin, and the functional phenotype of splenocytes and potential underlying mechanisms were investigated. Results: Metformin significantly boosts NK cell cytotoxicity and the per-centage of NKp46+, FasL+, and interferon (IFN)-gamma+ NK cells while decreasing interleukin (IL)-10 producing NK cells. Our research also demonstrated that the simultaneous administration of metformin and 1-methyl-DL-tryptophan (1 -MT), a specific inhibitor of indoleamine 2,3-dioxygenase (IDO), significantly increased the NK cells synthesis of IFN-gamma, IL-17, perforin, and FasL and NKp46 expression. These findings imply that metformin potentiates NK cell cytotoxicity through mechanisms other than IDO blockade. Metformin administration strongly increased the expression of im-munostimulatory microRNA (miRNA)-150 and miRNA-155, while decreasing the expression of immunosuppressive miRNA-146a. Conclusions: These findings suggest that metformin can directly potentiate NK cell activation and cytotoxicity. This research may contribute to dissecting key mechanisms of metformin exerting antitumor activity to advance the use of metformin as an antitumor agent.