Treatment of patients with hepatocellular carcinoma in the advanced stage remains a great challenge, with very few drugs approved. After decades of failures of immune therapies, immune checkpoint inhibitors have emerged as potentially effective treatments for patients with hepatocellular carcinoma in the advanced stage. Immune checkpoints, including human cancer, cytotoxic T-lymphocyte protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1), are surface proteins expressed in a variety of immune cells, and mostly provide immunosuppressive signals. Monoclonal antibodies able to block these molecules have shown antitumor activity against a wide spectrum of human cancers. Clinical experience with checkpoint inhibitors in hepatocellular carcinoma includes early trials with the anti-CTLA-4 agent tremelimumab, and a large phase 2 trial with the anti-PD-1 agent nivolumab. The latter has shown strong activity particularly as second-line therapy, both in terms of tumor response and patient survival. At least three topics should be the focus of future research. The search for activity in patients at less advanced stages, including the adjuvant treatment of patients with resectable or ablatable tumors. The enhanced efficacy of combination therapies, including particularly the combination with those targeted and locoregional therapies that may have a synergistic effect or act upon mechanisms of primary or acquired resistance to checkpoint inhibitors. And the identification of clinical features and serum or tissue biomarkers that would allow a better patient selection for individual treatments. Hopefully, ongoing trials will help design better treatments in the next future.
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