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‐γ and IL‐17A expression along with the transcription factors that drive their expression (T‐bet [Th1] and ROR‐γt [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.