Hepatocellular carcinoma (HCC) is the most common type of primary liver malignancy and the fourth leading cause of cancer-related deaths globally. HCC is often diagnosed in late stage, difficult to treat, and has poor prognosis with a median survival of 6-20 months. Innate and adaptive immunity play a pivotal role in determining tumor control versus progression. Genomic instability and abnormal signaling in the setting of chronic liver inflammation lead to tumorigenesis. Tumor progression occurs due to a sustained inflammatory response that promotes fibrogenesis and angiogenesis. This review discusses the key innate and adaptive cellular players that mediate the anti-tumor response. This review explores the complex interactions that occur within the tumor microenvironment and their clinical implications. HCC is a fastidious malignancy that is able to evade and downregulate the host immune response. Mechanisms of how this occurs are discussed, along with how they may be exploited in the development of novel therapeutics. From our research, it appears that striking a balance between immunotolerance and a robust immune response may yield the best prognosis. This review assesses major and recent developments in HCC immunotherapy, including adoptive cell therapy, cancer vaccines, and targeted therapy such as checkpoint inhibitors. Overall, the importance of the immune response in determining outcomes for HCC cannot be understated. Improved animal models and better characterization of the tumor microenvironment are needed. We determine that a better understanding of the HCC immune profile would facilitate advancements in diagnosis, monitoring, and ultimately treatment.
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