J Liver Cancer.  2019 Mar;19(1):1-11. 10.17998/jlc.19.1.1.

Recent Advances and Future Directions in Immunotherapeutics for Hepatocellular Carcinoma

  • 1Department of Internal Medicine, CHA Gangnam Medical Center, CHA University School of Medicine, Seoul, Korea.
  • 2Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea. drwon1@snu.ac.kr


Systemic target therapeutic drugs, such as sorafenib, lenvatinib, or regorafenib are the only drugs that are known to be effective against advanced hepatocellular carcinoma (HCC). However, these agents show a limited efficacy in killing residual tumors. Immunotherapy is an alternative approach to this treatment and has been used to successfully treat different cancers, including HCC. HCC is an inflammation-induced cancer and represents a very interesting target for immunotherapeutics. Immunotherapies aim to reverse the immune tolerance and suppression found in tumor microenvironments and include approaches, such as adoptive cell therapy, immune checkpoint inhibition, and cancer vaccination. Adoptive cell therapy uses autologous natural killer or cytokine-induced killer cells by cultivating them ex vivo and subsequently reinfusing them into the patient. Immune checkpoint inhibitors reactivate tumor-specific T cells by suppressing checkpoint-mediated inhibitory signaling. Cancer vaccination induces a tumor-specific immune response by activating effector T lymphocytes. A wide range of potential immunotherapy-related adverse events occur; therefore, a multidisciplinary collaborative management is required across the clinical spectrum. This review summarizes the current status of immunotherapy for HCC and provides a perspective on its future applications.


Hepatocellular carcinoma; Immunotherapy; Immune checkpoint inhibitor; Adoptive cell therapy; Oncolytic virus

MeSH Terms

Carcinoma, Hepatocellular*
Cell- and Tissue-Based Therapy
Cytokine-Induced Killer Cells
Immune Tolerance
Neoplasm, Residual
Oncolytic Viruses
Tumor Microenvironment


  • Figure 1. The three main strategies of HCC immunotherapy. HCC, hepatocellular carcinoma; NK, natural killer; CIK, cytokine-induced killer; DC, dendritic cells.

  • Figure 2. The structure of CAR. scFv, single chain fragment variable; ITAM, immunoreceptor tyrosine-based activation motif; CM, costimulatory molecules; CAR, chimeric antigen receptor.

  • Figure 3. Interaction between major immune co-stimulatory and inhibitory molecules and their cognate receptors. Co-stimulatory and co-inhibitory molecules are indicated by closed and open boxes, respectively. Costimulatory and inhibitory signals are indicated by filled and hatched arrows, respectively. APC, antigen presenting cell; PD, programmed cell death; CTLA, cytotoxic T lymphocyte antigen; LAG, lymphocyte activation gene; TIM, T cell immunoglobulin and mucin domain; MHC, major histocompatibility complex; SIPR = sphingosine-1-phosphate receptor.

  • Figure 4. Immunotherapy-related adverse events in multi-organs.


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