Theoretical Update of Cancer Evo-Dev and Its Role in Targeted Immunotherapy for Hepatocellular Carcinoma

Primary liver cancer (PLC) is the first leading cause of immature cancer death in China. Hepatocellular carcinoma (HCC) in China accounts for 93.0% of PLC. Chronic infection with hepatitis B virus (HBV) HCC contributes to 84.4% of HCC. During HBV-induced hepatocarcinogenesis, non-resolving inflammation facilitates viral and host genome mutations via the up-regulated expression of activation-induced cytidine deaminase/APOBEC3s and decreases mutation repair via the down-regulated expression of uracil DNA glycosylase by proinflammatory cytokines such as interleukin-6. The proinflammatory tumor microenvironment (TME) provides necessary conditions for the "mutation-selection-adaptation" evolutionary process of HBV and human hepatocytes and facilitates the retrodifferentiation of mutated hepatic cells. This evolutionary process has two prerequisites: driving somatic mutations and immune-suppressive TME. Cancer-promoting chromosome instability and viral mutations inhibit type I interferon signaling via activating the cyclic GMP-AMP synthase stimulator of interferon genes, induce immune-suppressive inflammation, and recruit immune-suppressive immune cells, including tumor-associated macrophages, regulatory T cells, and myeloid-derived suppressor cells, to build immunosuppressive TME. In the TME, the rapid growth of tumor cell-caused hypoxia activates kynurenine metabolism in the HCC tissues by inducing the expression of immune-suppressive inflammatory factors to promote the expression of PD-1 on regulatory T cells for enhanced immunosuppression; it also inhibits the cytotoxicities of CD8+T and natural killer cells and facilitates angiogenesis. The theoretical update of "Cancer Evo-Dev" highlights the direction of cancer prophylaxis and treatment. The treatments targeting angiogenesis significantly inhibit the growth of HCC, increase anti-tumoral immunity, and enhance the efficacy of immunotherapy. The combination of targeted therapy and immunotherapy should be the major therapeutic option for the treatment of advanced liver cancer.