Metformin decreases IL-22 secretion to suppress tumor growth in an orthotopic mouse model of hepatocellular carcinoma

Epidemiological, preclinical and cellular studies in the last 5 years have shown that metformin exerts anti-tumoral properties, but its mode of action in cancer remains unclear. Here, we investigated the effects of metformin on a mouse hepatocellular carcinoma (HCC) model and tumor-associated T cell immune responses. Oral metformin administration led to a significant reduction of tumor growth, which was accompanied by decreased interleukin-22 (IL-22). Meanwhile, IL-22-induced STAT3 phosphorylation and upregulation of downstream genes Bcl-2 and cyclin D1 were inhibited by metformin. At the cellular level, metformin attenuated Th1- and Th17-derived IL-22 production. Furthermore, metformin inhibited de novo generation of Th1 and Th17 cells from naive CD4(+) cells. These observations were further supported by the fact that metformin treatment inhibited CD3/CD28-induced IFN- and IL-17A expression along with the transcription factors that drive their expression (T-bet [Th1] and ROR-t [Th17], respectively). The effects of metformin on T cell differentiation were mediated by downregulated STAT3 and STAT4 phosphorylation via the AMP-activated kinase-mammalian target of rapamycin complex 1 pathway. Notably, metformin led to a reduction in glucose transporter Glut1 expression, resulting in less glucose uptake, which is critical to regulate CD4(+) T cell fate. Taken together, these findings provide evidence for the growth-inhibitory and immune-modulatory effects of metformin in HCC and thus, broaden our understanding about the action of metformin in liver cancer treatment. What's new? Over the last decade, metformin, an anti-diabetic drug, has gained significant attention as an anti-cancer drug because of its association with a dramatically decreased risk of some cancers. The underlying mechanisms of action, however, remain largely unknown. Here, using a mouse hepatocellular carcinoma (HCC) model, the authors found an important and previously unidentified effect of metformin with the inhibition of HCC growth through an indirect path mediated by IL-22. The findings also provide evidence for immune-modulatory effects of metformin in HCC. Taken together, these data broaden our current understanding of the mechanisms of action of metformin in liver cancer treatment.