Hot and Cold HCC: Uncoupling Viral Oncogenesis and Therapy

Hepatocellular carcinoma (HCC) is rising in incidence globally. It is the sixth most common cancer and the third leading cause of cancer-related mortality worldwide. Infection with hepatitis B and/or C virus is a significant risk factor for developing HCC. These viruses exert their carcinogenicity in both direct and indirect ways, including induction of immune exhaustion with prolonged antigen exposure. Therefore, the best therapeutic option for HCC is prevention, i.e., Hepatitis B vaccination and treatment of viral hepatitis. However, when HCC develops because of viral hepatitis or other etiologies, long-lasting effects on the immune system remain even after viral suppression, which affect the response to HCC therapy. Recent studies have suggested a "hot" and "cold" model for HCC, in which the two kinds of HCC tumors have very distinct tumor microenvironments. The microenvironment for hot HCC makes these tumors amenable to immunotherapy with checkpoint inhibitors. Therefore, converting cold HCC tumors to hot tumors may make them susceptible to immunotherapy. In this review, we provide an overview of HCC epidemiology and prevention, an overview of tumor microenvironments of hot and cold HCC, the proposed mechanisms for converting cold tumors to hot tumors, and a concise summary of the evidence for combination checkpoint inhibitor therapy for HCC.