Regulation of immune tolerance in hepatocellular carcinoma by liver diseases: a review

The clinical benefit of immunotherapy for hepatocellular carcinoma (HCC) is often limited by innate immune tolerance. Traditional research focuses on the intrinsic escape mechanism of tumor cells or the generalized immunosuppression of the tumor microenvironment; however, it often ignores the chronic liver disease background of HCC patients with different etiologies. The aim of this review was to systematically discuss the mechanisms by which different underlying liver diseases, particularly metabolic dysfunction associated steatohepatitis, viral hepatitis (hepatitis B virus/hepatitis C virus) and alcoholic liver disease, specifically shape the liver immune microenvironment, thereby driving HCC to develop tolerance to immune checkpoint inhibitors. We further explored the molecular mechanisms by which various etiologies promote T cell exhaustion, expand immunosuppressive cells, and change the function of the gut-liver axis through unique pathways, such as metabolic dysfunction-associated steatohepatitis-related metabolic disorders and dysbiosis, sustained antigen stimulation and epigenetic regulation of viral hepatitis, and the hyperinflammatory chemokine network of alcoholic liver disease. In addition, this article systematically evaluates the potential synergistic or antagonistic effects of drugs used to treat these underlying liver diseases (e.g., lipid-lowering drugs, liver protective drugs, antiviral drugs, antifibrotic drugs, and new metabolic targeted drugs) on HCC immunotherapy. The objectives are to provide key mechanistic insights and strategic references for clinical combination drugs, as well as emphasize the corresponding individualized immunotherapy strategies for HCC caused by different diseases.