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CC BY 4.0 · Semin Liver Dis
DOI: 10.1055/a-2334-8311
Review Article

Overcoming Resistance to Immune Checkpoint Blockade in Liver Cancer with Combination Therapy: Stronger Together?

Wiebke Werner
1   Department of Hepatology and Gastroenterology, Charité Universitaetsmedizin Berlin, Berlin, Germany
,
Maria Kuzminskaya
1   Department of Hepatology and Gastroenterology, Charité Universitaetsmedizin Berlin, Berlin, Germany
,
Isabella Lurje
1   Department of Hepatology and Gastroenterology, Charité Universitaetsmedizin Berlin, Berlin, Germany
,
Frank Tacke
1   Department of Hepatology and Gastroenterology, Charité Universitaetsmedizin Berlin, Berlin, Germany
,
Linda Hammerich
1   Department of Hepatology and Gastroenterology, Charité Universitaetsmedizin Berlin, Berlin, Germany
› Author Affiliations Funding This study was supported by the German Research Foundation (DFG; SPP2306 Ha7431/3-1, Ta434/8-1, SFB/TRR 296, and SFB1382, Project-ID 403224013), and the Else-Kröner-Fresenius-Stiftung (2021_EKEA.145).
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Abstract

Primary liver cancer, represented mainly by hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (CCA), is one of the most common and deadliest tumors worldwide. While surgical resection or liver transplantation are the best option in early disease stages, these tumors often present in advanced stages and systemic treatment is required to improve survival time. The emergence of immune checkpoint inhibitor (ICI) therapy has had a positive impact especially on the treatment of advanced cancers, thereby establishing immunotherapy as part of first-line treatment in HCC and CCA. Nevertheless, low response rates reflect on the usually cold or immunosuppressed tumor microenvironment of primary liver cancer. In this review, we aim to summarize mechanisms of resistance leading to tumor immune escape with a special focus on the composition of tumor microenvironment in both HCC and CCA, also reflecting on recent important developments in ICI combination therapy. Furthermore, we discuss how combination of ICIs with established primary liver cancer treatments (e.g. multikinase inhibitors and chemotherapy) as well as more complex combinations with state-of-the-art therapeutic concepts may reshape the tumor microenvironment, leading to higher response rates and long-lasting antitumor immunity for primary liver cancer patients.

Keywords

hepatocellular carcinoma - cholangiocarcinoma - immunotherapy - checkpoint inhibitors - resistance


Publication History

Accepted Manuscript online:
28 May 2024

Article published online:
21 June 2024

© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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