Immunotherapies for hepatocellular carcinoma

Josep M. Llovet*, Florian Castet, Mathias Heikenwalder, Mala K. Maini, Vincenzo Mazzaferro, David J. Pinato, Eli Pikarsky, Andrew X. Zhu, Richard S. Finn

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

744 Scopus citations


Liver cancer, more specifically hepatocellular carcinoma (HCC), is the second leading cause of cancer-related death and its incidence is increasing globally. Around 50% of patients with HCC receive systemic therapies, traditionally sorafenib or lenvatinib in the first line and regorafenib, cabozantinib or ramucirumab in the second line. In the past 5 years, immune-checkpoint inhibitors have revolutionized the management of HCC. The combination of atezolizumab and bevacizumab has been shown to improve overall survival relative to sorafenib, resulting in FDA approval of this regimen. More recently, durvalumab plus tremelimumab yielded superior overall survival versus sorafenib and atezolizumab plus cabozantinib yielded superior progression-free survival. In addition, pembrolizumab monotherapy and the combination of nivolumab plus ipilimumab have received FDA Accelerated Approval in the second-line setting based on early efficacy data. Despite these major advances, the molecular underpinnings governing immune responses and evasion remain unclear. The immune microenvironment has crucial roles in the development and progression of HCC and distinct aetiology-dependent immune features have been defined. Inflamed and non-inflamed classes of HCC and genomic signatures have been associated with response to immune-checkpoint inhibitors, yet no validated biomarker is available to guide clinical decision-making. This Review provides information on the immune microenvironments underlying the response or resistance of HCC to immunotherapies. In addition, current evidence from phase III trials on the efficacy, immune-related adverse events and aetiology-dependent mechanisms of response are described. Finally, we discuss emerging trials assessing immunotherapies across all stages of HCC that might change the management of this disease in the near future.

Original languageAmerican English
Pages (from-to)151-172
Number of pages22
JournalNature Reviews Clinical Oncology
Issue number3
StatePublished - Mar 2022

Bibliographical note

Publisher Copyright:
© 2021, Springer Nature Limited.


  • Carcinoma, Hepatocellular/drug therapy
  • Humans
  • Immune Checkpoint Inhibitors/therapeutic use
  • Immunotherapy
  • Liver Neoplasms/drug therapy
  • Sorafenib/therapeutic use
  • Tumor Microenvironment


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