Tumor Immune Microenvironment and Immunosuppressive Therapy in Hepatocellular Carcinoma: A Review

Int J Mol Sci. 2021 May 28;22(11):5801. doi: 10.3390/ijms22115801.


Liver cancer has the fourth highest mortality rate of all cancers worldwide, with hepatocellular carcinoma (HCC) being the most prevalent subtype. Despite great advances in systemic therapy, such as molecular-targeted agents, HCC has one of the worst prognoses due to drug resistance and frequent recurrence and metastasis. Recently, new therapeutic strategies such as cancer immunosuppressive therapy have prolonged patients' lives, and the combination of an immune checkpoint inhibitor (ICI) and VEGF inhibitor is now positioned as the first-line therapy for advanced HCC. Since the efficacy of ICIs depends on the tumor immune microenvironment, it is necessary to elucidate the immune environment of HCC to select appropriate ICIs. In this review, we summarize the findings on the immune microenvironment and immunosuppressive approaches focused on monoclonal antibodies against cytotoxic T lymphocyte-associated protein 4 and programmed cell death protein 1 for HCC. We also describe ongoing treatment modalities, including adoptive cell transfer-based therapies and future areas of exploration based on recent literature. The results of pre-clinical studies using immunological classification and animal models will contribute to the development of biomarkers that predict the efficacy of immunosuppressive therapy and aid in the selection of appropriate strategies for HCC treatment.

Keywords: adaptive cell transfer-based therapy; chimeric antigen receptor; chronic hepatitis; cytokine-induced killer; fibrosis; hepatocellular carcinoma; immune checkpoint inhibitor; immunotherapy; molecular target agent; tumor microenvironment.

Publication types

  • Review

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / immunology
  • Carcinoma, Hepatocellular / therapy*
  • Humans
  • Immune Checkpoint Inhibitors / therapeutic use*
  • Immunotherapy, Adoptive / methods*
  • Liver / drug effects*
  • Liver / immunology
  • Liver / pathology
  • Liver Neoplasms / immunology
  • Liver Neoplasms / therapy*
  • Neoplasm Recurrence, Local
  • T-Lymphocytes / immunology
  • Tumor Microenvironment / drug effects*
  • Tumor Microenvironment / immunology


  • Immune Checkpoint Inhibitors