Simple SummaryThe study investigates the potential use of metformin, a medication commonly prescribed for type 2 diabetes, in the treatment of hepatocellular carcinoma (HCC). Metformin has been gaining attention for its possible anticancer properties beyond its antidiabetic effects. The study explores the mechanisms through which metformin may exert its anticancer effects, including its impact on metabolic pathways, inflammation reduction and modulation of the tumor microenvironment. It also discusses the potential of combining metformin with immunotherapeutic approaches, such as immune checkpoint inhibitors, to enhance HCC treatment outcomes. While preliminary preclinical studies have shown promising results, further research and clinical trials are needed to determine the optimal dosage, treatment duration and patient selection criteria for metformin-including therapies. In conclusion, repurposing metformin for HCC immunotherapy presents a hopeful avenue for enhancing treatment options. Utilizing metformin’s immunomodulatory properties in combination with other therapeutic strategies could pave the way for more effective and tailored approaches to HCC treatment in the future.AbstractHepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. There has been significant progress in understanding the risk factors and epidemiology of HCC during the last few decades, resulting in efficient preventative, diagnostic and treatment strategies. Type 2 diabetes mellitus (T2DM) has been demonstrated to be a major risk factor for developing HCC. Metformin is a widely used hypoglycemic agent for patients with T2DM and has been shown to play a potentially beneficial role in improving the survival of patients with HCC. Experimental and clinical studies evaluating the outcomes of metformin as an antineoplastic drug in the setting of HCC were reviewed. Pre-clinical evidence suggests that metformin may enhance the antitumor effects of immune checkpoint inhibitors (ICIs) and reverse the effector T cells’ exhaustion. However, there is still limited clinical evidence regarding the efficacy of metformin in combination with ICIs for the treatment of HCC. We appraised and analyzed in vitro and animal studies that aimed to elucidate the mechanisms of action of metformin, as well as clinical studies that assessed its impact on the survival of HCC patients.