Oncogenic Signal and Tumor Microenvironment in Hepatocellular Carcinoma.

During tumor development, several immunosuppressive molecules are released from cancer cells and contribute to the establishment of immunosuppressive tumor environment. In tumor tissues, cytokines, chemokines, growth factors, and metabolites are present and could counter the effects of immune checkpoint inhibitors. From this point of view, monotherapy of anti-PD-1/PD-L1 antibody might not be enough to exert a sufficient antitumor effect; additional blockade of immunosuppressive molecules in tumor microenvironment could enhance the antitumor effect of anti-PD-1/PD-L1 antibody. Importantly, the production of immunosuppressive molecules in cancer cells is attributed to the activation of cellular signaling through genetic and epigenetic alterations and environmental stimulation, such as inflammation and hypoxia. In this review, we focus on the establishment of immunosuppressive microenvironment of hepatocellular carcinoma in the context of activation of oncogenic signals, and discuss how the immunosuppressive condition could be overcome using tyrosine kinase inhibitors.