Metformin's Role in Modulating the Tumor Microenvironment and Immune Response in Cancer Therapy

Metformin, a primary treatment for T2DM, is increasingly recognized for its anticancer properties, particularly its ability to modulate the TME and enhance antitumor immunity. By activating AMPK, metformin disrupts cancer metabolism, inhibits the PI3K/Akt/mTOR pathway, and reduces mitochondrial oxygen consumption, thereby alleviating tumor hypoxia. These metabolic shifts promote the infiltration of CD8+ and NK cells while reducing immunosuppressive populations such as Tregs and MDSCs. Furthermore, metformin facilitates the repolarization of TAMs from a pro-tumor M2 to an anti-tumor M1 phenotype. Clinical evidence suggests that metformin synergizes with chemotherapy, radiotherapy, and ICIs, offering a promising adjuvant strategy to overcome therapy resistance and improve patient outcomes. This review summarizes the molecular mechanisms and clinical potential of metformin in immunometabolic cancer therapy.