Clinical trials are currently ongoing to evaluate the utility of antibodies against programmed cell death 1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) as monotherapy or combination therapy in patients with hepatocellular carcinoma (HCC). Results of combination treatment with the anti-PD-L1 antibody durvalumab and the anti-CTLA-4 antibody tremelimumab in HCC were presented at the 2017 annual meeting of the ASCO (American Society of Clinical Oncology). Response rates were 25% in all 40 patients and 40% in the 20 uninfected patients, both of which are encouraging. Transcatheter arterial chemoembolization and radiofrequency ablation can activate tumor immunogenicity by releasing tumor-associated antigen and by inducing the migration of cytotoxic T lymphocytes to small intrahepatic metastatic nodules. Subsequent administration of anti-PD-1 antibody could control these small intrahepatic metastatic nodules. In a nonclinical study, the combination of pembrolizumab and lenvatinib inhibited the cancer immunosuppressive environments induced by tumor-associated macrophages and regulatory T cells. This, in turn, decreased the levels of TGF-β and IL-10, the expression of PD-1, and the inhibition of Tim-3, triggering anticancer immunity mediated by immunostimulatory cytokines such as IL-12. Studies such as these may provide insight into the appropriate molecular targeted agents to be used with immune checkpoint inhibitors.