Mol. Cell 71, 606–620 (2018)
Metformin is prescribed for type 2 diabetes, but anti-tumor effects have also been attributed to metformin. In Molecular Cell, Hung and colleagues show that metformin enhances the efficacy of CD8+ T cells by suppressing surface expression of the checkpoint inhibitor PD-L1 on tumor cells. This enhancement of cytotoxicity is dependent on expression of the energy sensor kinase AMPK in tumor cells. Metformin activates AMPK, which in turn phosphorylates newly synthesized PD-L1 within the ER lumen. This phosphorylation of PD-L1 leads to abnormal N-glycosylation of PD-L1 and blocks its maturation within the Golgi, instead triggering ER-associated degradation of PD-L1. Thus, metformin therapy makes tumor cells more vulnerable to cytotoxic T cells.
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Dempsey, L.A. Anti-tumor role of metformin. Nat Immunol 19, 1039 (2018). https://doi.org/10.1038/s41590-018-0224-x