**1. Introduction**

Hepatocellular carcinoma (HCC) is estimated to be the sixth most prevalent cancer worldwide and the fourth leading cause of cancer-related death [1]. HCC typically develops in the background of chronic liver disease often in the setting of either chronic infection with hepatitis B or C, alcohol abuse, or metabolic syndrome [2].

The immune system plays a vital role in controlling cancer development and progression [2]. Dysfunction of the tumor and immune system interaction leads to immune evasion through impaired antigen recognition or by tumor creating an immunosuppressive microenvironment [3]. Immune checkpoints are inhibitor molecules expressed by lymphocytes that prevent their overaction. Tumor cells exploit this normal physiological mechanism by expressing these ligands in the tumor microenvironment [4]. The recent emergence of immune checkpoint inhibitors has significantly changed the cancer treatment landscape. These monoclonal antibodies block the interaction of checkpoint proteins with their ligands, preventing the inactivation of T cells [5]. The ligands that are targeted include cytotoxic T lymphocyteassociated antigen (CTLA4), programmed death 1 (PD-1), programmed death-ligand 1 (PD-L1), lymphocyte-activation gene 3 (LAG3), etc. [6].

Immune checkpoint inhibitors have had promising results in patients with advanced hepatocellular carcinoma due to the contribution of inflammation and suppression of immune microenvironments to HCC pathogenesis, becoming essential in HCC management [7, 8].

In this chapter, we will review the major immunotherapy trials in patients with advanced HCC in both the firstline and subsequent line setting as well as discuss the mechanism of immune mediated side effects in these patients. We will also discuss the emerging role of immunotherapy in transplant patients.
