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. 2025 Jan 1;15(3):993–1016. doi: 10.7150/thno.104872

Figure 1.

Figure 1

Schematic illustration of the mechanism of inhibiting tumor cell growth and reprogramming the TME by metformin. Metformin inhibits mitochondrial complex I, reducing oxygen consumption in tumor cells and alleviating hypoxia in the TME. Metformin-induced AMPK activation leads to mTORC1 inhibition in tumor cells, thus reducing glycolysis, protein synthesis and lipid synthesis. The AMPK pathway activation in tumor cells also inhibits the secretion of immunosuppressive cytokines, which facilitates M1-to-M2 polarization of TAMs. Besides, AMPK activation in tumor cells induces abnormal glycosylation and proteasomal degradation of PD-L1 proteins. Downregulated PD-L1 expression on tumor cells weakens the immunosuppressive signal from PD-L1/PD-1 engagement, thus enhancing CD8+ T cell cytotoxicity. Created in https://BioRender.com. AMPK: adenosine monophosphate-activated protein kinase; eIF4E: eukaryotic initiation factor 4E; HIF-1α: hypoxia inducible factor-1α; LKB1: liver kinase B1; mTORC1: mammalian target of rapamycin complex 1; NF-κB: nuclear factor kappa-B; PD-L1: programmed cell death 1 ligand 1; PD-1: programmed cell death 1; S6K: ribosomal protein S6 kinase; SREBP: sterol regulatory element-binding protein; TME: tumor microenvironment.