Significance: Hepatocellular carcinoma (HCC) is a liver malignancy with high mortality rate, limited treatment options, and poor prognosis. Sorafenib has been the only systemic treatment option for patients with advanced HCC for more than a decade. HCC is a typical inflammation-related tumor with a distinct immunosuppressive microenvironment especially the upregulation of immune checkpoints. Recent Advances: Immunotherapy has shown persistent and powerful efficacy in HCC treatment. Several preclinical and clinical studies have prompted the application of immunotherapy in first-line, second-line, and postline treatment of HCC, which has profoundly shifted the paradigm for advanced HCC treatment in the past few years. Critical Issues and Future Directions: Major unaddressed challenges in HCC immunotherapy include the discovery and validation of biological markers that predict the efficacy, the application of immunotherapy in patients with impaired liver function and nonalcoholic steatohepatitis-associated HCC, and the exploration of immunotherapy combinations with better effectiveness. This review provides the latest advances in the research of immune microenvironment and immunotherapy in HCC. Antioxid. Redox Signal. 37, 1325-1338.
Keywords: PD-1/PD-L1; hepatocellular carcinoma; immunotherapy; tumor microenvironment.