New insights into the pathogenesis and treatment of non-viral hepatocellular carcinoma: a balancing act between immunosuppression and immunosurveillance.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. HCC initiates as a consequence of chronic liver damage and inflammation caused by hepatitis B and C virus infections, excessive alcohol consumption, or non-alcoholic fatty liver disease (NAFLD). Until recently, no effective treatments for advanced HCC were available and the 5-year survival rate had remained below 8% for many years. New insights into the mechanisms that drive the development of NAFLD-related HCC indicate that loss of T-cell-mediated immunosurveillance plays a cardinal role in tumor growth and malignant progression, in addition to previously identified inflammation-driven compensatory proliferation. Recently completed groundbreaking clinical studies have shown that treatments that restore antitumor immunity represent a highly effective therapeutic option for approximately 20% of advanced HCC patients. Understanding the causes of inflammation-driven immunosuppression and immune system dysfunction in the 80% of patients who fail to reignite antitumor immunity despite treatment with checkpoint inhibitors should lead to further and even more dramatic improvements in HCC immunotherapy.