Metformin enhances TRAIL-mediated antitumor activity of liver natural killer cells in mice

Metformin exerts antitumor activity across multiple cancers, largely attributed to anti-inflammatory effects and the AMP-activated protein kinase (AMPK)-mediated inhibition of mammalian target of rapamycin (mTOR). However, the effects of metformin on intrahepatic immunity remain poorly defined. We previously demonstrated that mTOR inhibition augments the antitumor function of liver natural killer (NK) cells by upregulating tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Here, we investigated whether metformin modulates TRAIL expression on liver NK cells. Compared with vehicle control, metformin increased the proportion of TRAIL+ liver NK cells, enhanced the cytotoxicity of liver NK cells against TRAIL-sensitive tumor targets, and suppressed tumor growth in vivo. Mechanistically, metformin increased, by downregulating Eomes expression, the proportion of liver-resident NK cells (also known as type 1 innate lymphoid cells) which are an immature, TRAILhigh subset. Moreover, activation of the AMPK signaling axis may contribute to metformin-induced promotion of TRAIL+ liver NK cells. These findings indicate that metformin potentiates the antitumor activity of liver NK cells via TRAIL upregulation, supporting its potential repositioning as an immunomodulatory adjuvant for liver cancer.