Heterogeneous responses in hepatocellular carcinoma: the achilles heel of immune checkpoint inhibitors.

Treatment of patients with hepatocellular carcinoma (HCC) remains a serious challenge due to high heterogeneity and limited treatment options. In the past few decades, immune therapy, especially immune checkpoint therapy, has become an alternative option for the treatment of malignancies including HCC. Immune checkpoint inhibitors (ICIs) have raised attention because of their significant antitumor effect and low toxicity. However, such immunotherapy fails to be responsive in a major proportion of patients with HCC. Recent studies suggest that failures in antigen presentation, an impaired immune microenvironment, alterations in immune checkpoint molecules and immune-suppressive cells are responsible for the heterogeneous responses and resistance. Based on the specific characteristics above, we proposed a model stratifying patients with HCC into two subtypes that could predict response or resistance to ICI. Furthermore, supplementing ICIs with agents targeting the microenvironment could achieve an increased response rate, which is a step forward in precision treatment for HCC. In addition, emerging studies have revealed that liver transplantation, epigenetic drugs and other novel strategies also provide synergistic effects with ICIs in the treatment of HCC.