Role of β-Catenin Activation in the Tumor Immune Microenvironment and Immunotherapy of Hepatocellular Carcinoma

SIMPLE SUMMARY: The response rate to immune checkpoint inhibitor (ICI) monotherapy in hepatocellular carcinoma (HCC) is as low as 20%; therefore, it is important to identify the patient subgroups that respond to ICI. β-catenin activation is considered to be a key factor of ICI resistance. β-catenin activation is involved in immunologically cold tumor formation in the tumor microenvironment. Overall, controlling β-catenin activation may improve response rates of HCC tumors to ICI. β-catenin modulators and certain kinase inhibitors can suppress β-catenin activation; therefore, combining these drugs with ICIs is expected to further improve the therapeutic effect of ICIs in HCC. ABSTRACT: Recently, the therapeutic combination of atezolizumab and bevacizumab was widely used to treat advanced hepatocellular carcinoma (HCC). According to recent clinical trials, immune checkpoint inhibitors (ICIs) and molecular target agents are expected to be key therapeutic strategies in the future. Nonetheless, the mechanisms underlying molecular immune responses and immune evasion remain unclear. The tumor immune microenvironment plays a vital role in HCC progression. The infiltration of CD8-positive cells into tumors and the expression of immune checkpoint molecules are key factors in this immune microenvironment. Specifically, Wnt/β catenin pathway activation causes “immune exclusion”, associated with poor infiltration of CD8-positive cells. Some clinical studies suggested an association between ICI resistance and β-catenin activation in HCC. Additionally, several subclassifications of the tumor immune microenvironment were proposed. The HCC immune microenvironment can be broadly divided into inflamed class and non-inflamed class, with several subclasses. β-catenin mutations are important factors in immune subclasses; this may be useful when considering therapeutic strategies as β-catenin activation may serve as a biomarker for ICI. Various types of β-catenin modulators were developed. Several kinases may also be involved in the β-catenin pathway. Therefore, combinations of β-catenin modulators, kinase inhibitors, and ICIs may exert synergistic effects.