Metformin Enhances the Antitumor Activity of CD8+ T Lymphocytes via the AMPK–miR-107–Eomes–PD-1 Pathway

Abstract

Metformin has been studied for its anticancer effects by regulating T cell functions. However, the mechanisms through which metformin stimulates the differentiation of memory T cells remain unclear. We found that the frequencies of memory stem and central memory T cells increased for both in peripheral and tumor-infiltrating CD8⁺ T cells in metformin-treated lung cancer patients compared with those not taking the medication. An in vitro assay showed that metformin promoted the formation of memory CD8⁺ T cells and enhanced their antiapoptotic abilities. In addition, AMP-activated protein kinase (AMPK) activation decreased microRNA-107 expression, thus enhancing Eomesodermin expression, which suppressed the transcription of <i>PDCD1</i> in metformin-treated CD8⁺ T cells. In the CAR-T cell therapy model, metformin also exhibited cytotoxicity-promoting effects that led to decreased tumor growth. Metformin could reprogram the differentiation of CD8⁺ T cells, which may benefit the clinical therapy of cancer patients by facilitating long-lasting cytotoxic functions.