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The immunological and metabolic landscape in primary and metastatic liver cancer

Abstract

The liver is the sixth most common site of primary cancer in humans, and generally arises in a background of cirrhosis and inflammation. Moreover, the liver is frequently colonized by metastases from cancers of other organs (particularly the colon) because of its anatomical location and organization, as well as its unique metabolic and immunosuppressive environment. In this Review, we discuss how the hepatic microenvironment adapts to pathologies characterized by chronic inflammation and metabolic alterations. We illustrate how these immunological or metabolic changes alter immunosurveillance and thus hinder or promote the development of primary liver cancer. In addition, we describe how inflammatory and metabolic niches affect the spreading of cancer metastases into or within the liver. Finally, we review the current therapeutic options in this context and the resulting challenges that must be surmounted.

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Fig. 1: The immune microenvironment of the healthy, inflamed and cancerous liver.
Fig. 2: The metabolic microenvironment of the healthy and inflamed liver.
Fig. 3: Liver cell plasticity and oncogenic transformation.
Fig. 4: The immunometabolic microenvironment of cancerous liver.
Fig. 5: The prometastatic and antimetastatic microenvironment of the liver.

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Acknowledgements

The authors thank S. Gallage for his critical proofreading of the manuscript. M.H. was supported by an European Research Council (ERC) Consolidator grant (HepatoMetaboPath), SFBTR179 project ID 272983813, SFB/TR 209 project ID 314905040, SFBTR1335 project ID 360372040, SFB 1479 (Project ID: 441891347), the Wilhelm Sander-Stiftung, the Rainer Hoenig Stiftung, a Horizon 2020 grant (Hepcar), Research Foundation Flanders (FWO) under grant 30826052 (EOS Convention MODEL-IDI), Deutsche Krebshilfe projects 70113166 and 70113167, German-Israeli Cooperation in Cancer Research (DKFZ-MOST) and the Helmholtz-Gemeinschaft, Zukunftsthema ‘Immunology and Inflammation’ (ZT-0027).

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Glossary

Necro-inflammation

A pathological condition characterized by cell death (necrosis) that triggers the activation of the immune system, thereby sustaining a local inflammatory response.

Liver sinusoids

Specific capillaries characterized by a particular distribution of endothelial cells presenting a typical fenestration that enables arterial and venous blood to mix.

Steatosis

Abnormal cytosolic accumulation of lipids in more than 5% of the total hepatocyte content in the liver.

Nonalcoholic fatty liver disease

(NAFLD). Metabolic disease of the liver related to abnormal accumulation of lipids, encompassing a wide spectrum of pathologies from simple fatty liver to nonalcoholic steatohepatitis (characterized by hepatic inflammatory infiltrate (steatohepatitis)), fibrosis and cirrhosis.

Natural killer T cells

A heterogeneous population of T cells that share characteristics of classical T cells and natural killer cells. Their classical function relates to antibacterial activity; upon activation, they produce large amounts of interferon-γ (IFNγ), IL-4 and many other cytokines.

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Li, X., Ramadori, P., Pfister, D. et al. The immunological and metabolic landscape in primary and metastatic liver cancer. Nat Rev Cancer 21, 541–557 (2021). https://doi.org/10.1038/s41568-021-00383-9

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