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.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Macrophage-Derived MMP-9 and MMP-2 are Closely Related to the Rupture of the Fibrous Capsule of Hepatocellular Carcinoma Leading to Tumor Invasion
Biological Procedures Online Open Access 14 March 2023
SOTIP is a versatile method for microenvironment modeling with spatial omics data
Nature Communications Open Access 28 November 2022
AADAC protects colorectal cancer liver colonization from ferroptosis through SLC7A11-dependent inhibition of lipid peroxidation
Journal of Experimental & Clinical Cancer Research Open Access 26 September 2022
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 per month
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Rent or buy this article
Get just this article for as long as you need it
Prices may be subject to local taxes which are calculated during checkout
Llovet, J. M. et al. Hepatocellular carcinoma. Nat. Rev. Dis. Prim. 7, 6 (2021). This article provides the latest progress in the pathogenic mechanisms of HCC and its therapy.
Ringelhan, M., Pfister, D., O’Connor, T., Pikarsky, E. & Heikenwalder, M. The immunology of hepatocellular carcinoma. Nat. Immunol. 19, 222–232 (2018).
Keenan, B. P., Fong, L. & Kelley, R. K. Immunotherapy in hepatocellular carcinoma: the complex interface between inflammation, fibrosis, and the immune response. J. Immunother. Cancer 7, 1–13 (2019).
Kanwal, F. et al. Risk of hepatocellular cancer in patients with non-alcoholic fatty liver disease. Gastroenterology 155, 1828–1837.e2 (2018).
Protzer, U., Maini, M. K. & Knolle, P. A. Living in the liver: hepatic infections. Nat. Rev. Immunol. 12, 201–213 (2012).
European Association for the Study of the Liver. EASL clinical practice guidelines: management of hepatocellular carcinoma. J. Hepatol. 69, 182–236 (2018).
Carrat, F. et al. Clinical outcomes in patients with chronic hepatitis C after direct-acting antiviral treatment: a prospective cohort study. Lancet 393, 1453–1464 (2019).
Anstee, Q. M., Reeves, H. L., Kotsiliti, E., Govaere, O. & Heikenwalder, M. From NASH to HCC: current concepts and future challenges. Nat. Rev. Gastroenterol. Hepatol. 16, 411–428 (2019).
Steeg, P. S. Tumor metastasis: mechanistic insights and clinical challenges. Nat. Med. 12, 895–904 (2006).
Milette, S., Sicklick, J. K., Lowy, A. M. & Brodt, P. Molecular pathways: targeting the microenvironment of liver metastases. Clin. Cancer Res. 23, 6390–6399 (2017).
de Ridder, J. et al. Incidence and origin of histologically confirmed liver metastases: an explorative case-study of 23,154 patients. Oncotarget 7, 55368–55376 (2016).
Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2020. CA Cancer J. Clin. 70, 7–30 (2020).
Abou-Alfa, G. K. et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N. Engl. J. Med. 379, 54–63 (2018).
Llovet, J. M., Montal, R. & Villanueva, A. Randomized trials and endpoints in advanced HCC: role of PFS as a surrogate of survival. J. Hepatol. 70, 1262–1277 (2019).
Llovet, J. M. et al. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 359, 378–390 (2008).
Nault, J. C., Cheng, A. L., Sangro, B. & Llovet, J. M. Milestones in the pathogenesis and management of primary liver cancer. J. Hepatol. 72, 209–214 (2020). This paper summarizes important events in the medical history of primary liver cancer and discusses the most current discoveries.
Rizvi, S., Khan, S. A., Hallemeier, C. L., Kelley, R. K. & Gores, G. J. Cholangiocarcinoma — evolving concepts and therapeutic strategies. Nat. Rev. Clin. Oncol. 15, 95–111 (2018).
Vogel, A. et al. Hepatocellular carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 29, iv238–iv255 (2018).
Mizukoshi, E. & Kaneko, S. Immune cell therapy for hepatocellular carcinoma. J. Hematol. Oncol. 12, 52 (2019).
Kudo, M. Combination cancer immunotherapy in hepatocellular carcinoma. Liver Cancer 7, 20–27 (2018).
Heymann, F. et al. Liver inflammation abrogates immunological tolerance induced by Kupffer cells. Hepatology 62, 279–291 (2015).
Jenne, C. N. & Kubes, P. Immune surveillance by the liver. Nat. Immunol. 14, 996–1006 (2013).
Knolle, P. A. & Thimme, R. Hepatic immune regulation and its involvement in viral hepatitis infection. Gastroenterology 146, 1193–1207 (2014).
Winau, F. et al. Ito cells are liver-resident antigen-presenting cells for activating T cell responses. Immunity 26, 117–129 (2007).
Thomson, A. W. & Knolle, P. A. Antigen-presenting cell function in the tolerogenic liver environment. Nat. Rev. Immunol. 10, 753–766 (2010).
Thomson, A. W., Vionnet, J. & Sanchez-Fueyo, A. Understanding, predicting and achieving liver transplant tolerance: from bench to bedside. Nat. Rev. Gastroenterol. Hepatol. 17, 719–739 (2020).
Krueger, P. D., Kim, T. S., Sung, S. S., Braciale, T. J. & Hahn, Y. S. Liver-resident CD103+ dendritic cells prime antiviral CD8+ T cells in situ. J. Immunol. 194, 3213–3222 (2015).
Deczkowska, A. et al. XCR1+ type 1 conventional dendritic cells drive liver pathology in non-alcoholic steatohepatitis. Nat. Med. 27, 1043–1054 (2021).
Peng, H. et al. Liver-resident NK cells confer adaptive immunity in skin-contact inflammation. J. Clin. Invest. 123, 1444–1456 (2013).
Paust, S. et al. Critical role for the chemokine receptor CXCR6 in NK cell-mediated antigen-specific memory of haptens and viruses. Nat. Immunol. 11, 1127–1135 (2010).
Lassen, M. G., Lukens, J. R., Dolina, J. S., Brown, M. G. & Hahn, Y. S. Intrahepatic IL-10 maintains NKG2A+Ly49− liver NK cells in a functionally hyporesponsive state. J. Immunol. 184, 2693–2701 (2010).
Hoechst, B. et al. Myeloid derived suppressor cells inhibit natural killer cells in patients with hepatocellular carcinoma via the NKp30 receptor. Hepatology 50, 799–807 (2009).
Gabrilovich, D. I. & Nagaraj, S. Myeloid-derived suppressor cells as regulators of the immune system. Nat. Rev. Immunol. 9, 162–174 (2009).
Curiel, T. J. Tregs and rethinking cancer immunotherapy. J. Clin. Invest. 117, 1167–1174 (2007).
Diehl, L. et al. Tolerogenic maturation of liver sinusoidal endothelial cells promotes B7-homolog 1-dependent CD8+ T cell tolerance. Hepatology 47, 296–305 (2008).
Limmer, A. et al. Efficient presentation of exogenous antigen by liver endothelial cells to CD8+ T cells results in antigen-specific T-cell tolerance. Nat. Med. 6, 1348–1354 (2000).
Aizarani, N. et al. A human liver cell atlas reveals heterogeneity and epithelial progenitors. Nature 572, 199–204 (2019).
Peng, W. C. et al. Inflammatory cytokine TNFα promotes the long-term expansion of primary hepatocytes in 3D culture. Cell 175, 1607–1619.e15 (2018).
Berndt, N. et al. Functional consequences of metabolic zonation in murine livers: insights for an old story. Hepatology 73, 795–810 (2021).
Halpern, K. B. et al. Single-cell spatial reconstruction reveals global division of labour in the mammalian liver. Nature 542, 352–356 (2017).
Droin, C. et al. Space–time logic of liver gene expression at sub-lobular scale. Nat. Metab. 3, 43–58 (2021). This article reveals how liver function is compartmentalized spatiotemporally at the sub-lobular scale.
Planas-Paz, L. et al. The RSPO–LGR4/5–ZNRF3/RNF43 module controls liver zonation and size. Nat. Cell Biol. 18, 467–479 (2016).
Inverso, D. et al. A spatial vascular transcriptomic, proteomic, and phosphoproteomic atlas unveils an angiocrine Tie–Wnt signaling axis in the liver. Dev. Cell 56, 1677–1693.e10 (2021).
Keegan, A., Martini, R. & Batey, R. Ethanol-related liver injury in the rat: a model of steatosis, inflammation and pericentral fibrosis. J. Hepatol. 23, 591–600 (1995).
Hall, Z. et al. Lipid zonation and phospholipid remodeling in nonalcoholic fatty liver disease. Hepatology 65, 1165–1180 (2017).
Michelotti, G. A., Machado, M. V. & Diehl, A. M. NAFLD, NASH and liver cancer. Nat. Rev. Gastroenterol. Hepatol. 10, 656–665 (2013).
Lackner, C. Hepatocellular ballooning in nonalcoholic steatohepatitis: the pathologist’s perspective. Expert Rev. Gastroenterol. Hepatol. 5, 223–231 (2011).
Malehmir, M. et al. Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer. Nat. Med. 25, 641–655 (2019). This paper provides a rationale for antiplatelet therapy in reverting NASH and preventing NASH-to-HCC transition.
Wolf, M. J. et al. Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes. Cancer Cell 26, 549–564 (2014).
Kietzmann, T. Liver zonation in health and disease: hypoxia and hypoxia-inducible transcription factors as concert masters. Int. J. Mol. Sci. 20, 2347 (2019).
Kudo, Y. et al. PKCλ/ι loss induces autophagy, oxidative phosphorylation, and NRF2 to promote liver cancer progression. Cancer Cell 38, 247–262.e11 (2020).
Wilson, G. K., Tennant, D. A. & McKeating, J. A. Hypoxia inducible factors in liver disease and hepatocellular carcinoma: current understanding and future directions. J. Hepatol. 61, 1397–1406 (2014).
Wing, P. A. C. et al. Hypoxia inducible factors regulate hepatitis B virus replication by activating the basal core promoter. J. Hepatol. 75, 64–73 (2021).
Moreau, M. et al. Hepatitis C viral proteins perturb metabolic liver zonation. J. Hepatol. 62, 278–285 (2015).
Gautheron, J. et al. A positive feedback loop between RIP3 and JNK controls non-alcoholic steatohepatitis. EMBO Mol. Med. 6, 1062–1074 (2014).
Boege, Y. et al. A dual role of caspase-8 in triggering and sensing proliferation-associated DNA damage, a key determinant of liver cancer development. Cancer Cell 32, 342–359.e10 (2017). This article illustrates diverging mechanistic links of caspase 8 to cancer biology in the liver.
Holze, C. et al. Oxeiptosis, a ROS-induced caspase-independent apoptosis-like cell-death pathway. Nat. Immunol. 19, 130–140 (2018).
Seehawer, M. et al. Necroptosis microenvironment directs lineage commitment in liver cancer. Nature 562, 69–75 (2018). This article sheds light on lineage commitment during liver carcinogenesis and elucidates the molecular basis for common liver-damaging risk factors that result in either HCC or CCA.
Faubion, W. A. et al. Toxic bile salts induce rodent hepatocyte apoptosis via direct activation of Fas. J. Clin. Invest. 103, 137–145 (1999).
Brenner, C., Galluzzi, L., Kepp, O. & Kroemer, G. Decoding cell death signals in liver inflammation. J. Hepatol. 59, 583–594 (2013).
Asselah, T. et al. In vivo hepatic endoplasmic reticulum stress in patients with chronic hepatitis C. J. Pathol. 221, 264–274 (2010).
Merquiol, E. et al. HCV causes chronic endoplasmic reticulum stress leading to adaptation and interference with the unfolded protein response. PLoS ONE 6, e24660 (2011).
Roos, W. P., Thomas, A. D. & Kaina, B. DNA damage and the balance between survival and death in cancer biology. Nat. Rev. Cancer 16, 20–33 (2016).
Brumatti, G., Salmanidis, M. & Ekert, P. G. Crossing paths: interactions between the cell death machinery and growth factor survival signals. Cell Mol. Life Sci. 67, 1619–1630 (2010).
Farazi, P. A. & DePinho, R. A. Hepatocellular carcinoma pathogenesis: from genes to environment. Nat. Rev. Cancer 6, 674–687 (2006).
Roychowdhury, S., McMullen, M. R., Pisano, S. G., Liu, X. & Nagy, L. E. Absence of receptor interacting protein kinase 3 prevents ethanol-induced liver injury. Hepatology 57, 1773–1783 (2013).
Linkermann, A., Stockwell, B. R., Krautwald, S. & Anders, H. J. Regulated cell death and inflammation: an auto-amplification loop causes organ failure. Nat. Rev. Immunol. 14, 759–767 (2014).
Newton, K. et al. Cleavage of RIPK1 by caspase-8 is crucial for limiting apoptosis and necroptosis. Nature 574, 428–431 (2019).
Upton, J. W., Kaiser, W. J. & Mocarski, E. S. DAI/ZBP1/DLM-1 complexes with RIP3 to mediate virus-induced programmed necrosis that is targeted by murine cytomegalovirus vIRA. Cell Host Microbe 11, 290–297 (2012).
Li, J. et al. The RIP1/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis. Cell 150, 339–350 (2012).
Murphy, J. M. et al. The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism. Immunity 39, 443–453 (2013).
Malhi, H., Gores, G. J. & Lemasters, J. J. Apoptosis and necrosis in the liver: a tale of two deaths? Hepatology 43, S31–S44 (2006).
Caesar, R. et al. Gut-derived lipopolysaccharide augments adipose macrophage accumulation but is not essential for impaired glucose or insulin tolerance in mice. Gut 61, 1701–1707 (2012).
Sutti, S. et al. Adaptive immune responses triggered by oxidative stress contribute to hepatic inflammation in NASH. Hepatology 59, 886–897 (2014).
Sutti, S. & Albano, E. Adaptive immunity: an emerging player in the progression of NAFLD. Nat. Rev. Gastroenterol. Hepatol. 17, 81–92 (2020).
Wang, H. et al. TNF-α/IFN-γ profile of HBV-specific CD4 T cells is associated with liver damage and viral clearance in chronic HBV infection. J. Hepatol. 72, 45–56 (2020).
Grivennikov, S. I., Greten, F. R. & Karin, M. Immunity, inflammation, cancer. Cell 140, 883–899 (2010).
Kopp, J. L., Grompe, M. & Sander, M. Stem cells versus plasticity in liver and pancreas regeneration. Nat. Cell Biol. 18, 238–245 (2016).
Yanger, K. et al. Robust cellular reprogramming occurs spontaneously during liver regeneration. Genes Dev. 27, 719–724 (2013).
Sakurai, T. et al. Hepatocyte necrosis induced by oxidative stress and IL-1α release mediate carcinogen-induced compensatory proliferation and liver tumorigenesis. Cancer Cell 14, 156–165 (2008).
Flecken, T. et al. Immunodominance and functional alterations of tumor-associated antigen-specific CD8+ T-cell responses in hepatocellular carcinoma. Hepatology 59, 1415–1426 (2014).
Macdonald, R. Lifespan of liver cells — autoradiographic study using tritiated thymidine in normal, cirrhotic, and partially hepatectomized rats. Arch. Intern. Med. 107, 335–343 (1961).
Karin, M. & Clevers, H. Reparative inflammation takes charge of tissue regeneration. Nature 529, 307–315 (2016).
Yuan, D. T. et al. Kupffer cell-derived Tnf triggers cholangiocellular tumorigenesis through JNK due to chronic mitochondrial dysfunction and ROS. Cancer Cell 31, 771–789 (2017).
Pikarsky, E. et al. NF-κB functions as a tumour promoter in inflammation-associated cancer. Nature 431, 461–466 (2004).
Park, E. J. et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 140, 197–208 (2010).
Finkin, S. et al. Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma. Nat. Immunol. 16, 1235–1244 (2015).
Takai, A. et al. A novel mouse model of hepatocarcinogenesis triggered by AID causing deleterious p53 mutations. Oncogene 28, 469–478 (2009).
Marrogi, A. J. et al. Oxidative stress and p53 mutations in the carcinogenesis of iron overload-associated hepatocellular carcinoma. J. Natl Cancer Inst. 93, 1652–1655 (2001).
Elinav, E. et al. Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat. Rev. Cancer 13, 759–771 (2013).
Stauffer, J. K., Scarzello, A. J., Jiang, Q. & Wiltrout, R. H. Chronic inflammation, immune escape, and oncogenesis in the liver: a unique neighborhood for novel intersections. Hepatology 56, 1567–1574 (2012).
Grohmann, M. et al. Obesity drives STAT-1-dependent NASH and STAT-3-dependent HCC. Cell 175, 1289–1306.e20 (2018). This article demonstrates that obesity-related hepatic oxidative stress might contribute independently to the aetiology of NASH, fibrosis and HCC.
Xue, R. et al. Genomic and transcriptomic profiling of combined hepatocellular and intrahepatic cholangiocarcinoma reveals distinct molecular subtypes. Cancer Cell 35, 932–947.e8 (2019). This paper demonstrates that combined and mixed forms of HCC–CCA exhibit distinct clinical and molecular characteristics and identifies Nestin as a potential marker for diagnosis of HCC–CCA.
Mu, X. et al. Hepatocellular carcinoma originates from hepatocytes and not from the progenitor/biliary compartment. J. Clin. Invest. 125, 3891–3903 (2015).
Sia, D., Villanueva, A., Friedman, S. L. & Llovet, J. M. Liver cancer cell of origin, molecular class, and effects on patient prognosis. Gastroenterology 152, 745–761 (2017).
Ko, S., Russell, J. O., Molina, L. M. & Monga, S. P. Liver progenitors and adult cell plasticity in hepatic injury and repair: knowns and unknowns. Annu. Rev. Pathol. 15, 23–50 (2020).
Marquardt, J. U., Andersen, J. B. & Thorgeirsson, S. S. Functional and genetic deconstruction of the cellular origin in liver cancer. Nat. Rev. Cancer 15, 653–667 (2015).
Okabe, H. et al. Wnt signaling regulates hepatobiliary repair following cholestatic liver injury in mice. Hepatology 64, 1652–1666 (2016).
Hyun, J. et al. Dysregulated activation of fetal liver programme in acute liver failure. Gut 68, 1076–1087 (2019).
Komuta, M. et al. Histological diversity in cholangiocellular carcinoma reflects the different cholangiocyte phenotypes. Hepatology 55, 1876–1888 (2012).
Banales, J. M. et al. Expert consensus document: cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA). Nat. Rev. Gastroenterol. Hepatol. 13, 261–280 (2016).
Komuta, M. et al. Clinicopathological study on cholangiolocellular carcinoma suggesting hepatic progenitor cell origin. Hepatology 47, 1544–1556 (2008).
Brunt, E. et al. cHCC-CCA: consensus terminology for primary liver carcinomas with both hepatocytic and cholangiocytic differentation. Hepatology 68, 113–126 (2018).
Satriano, L., Lewinska, M., Rodrigues, P. M., Banales, J. M. & Andersen, J. B. Metabolic rearrangements in primary liver cancers: cause and consequences. Nat. Rev. Gastroenterol. Hepatol. 16, 748–766 (2019). This review discusses the impact of metabolic liver disturbances and the effects on primary liver cancer.
Yamashita, T. et al. Activation of lipogenic pathway correlates with cell proliferation and poor prognosis in hepatocellular carcinoma. J. Hepatol. 50, 100–110 (2009).
Wang, M. et al. Dysregulated fatty acid metabolism in hepatocellular carcinoma. Hepat. Oncol. 3, 241–251 (2016).
Xia, S., Pan, Y., Liang, Y., Xu, J. & Cai, X. The microenvironmental and metabolic aspects of sorafenib resistance in hepatocellular carcinoma. EBioMedicine 51, 102610 (2020).
Ma, M. K. F. et al. Stearoyl-CoA desaturase regulates sorafenib resistance via modulation of ER stress-induced differentiation. J. Hepatol. 67, 979–990 (2017).
Rudalska, R. et al. LXRα activation and Raf inhibition trigger lethal lipotoxicity in liver cancer. Nat. Cancer 2, 201–217 (2021).
Lally, J. S. V. et al. Inhibition of acetyl-CoA carboxylase by phosphorylation or the inhibitor ND-654 suppresses lipogenesis and hepatocellular carcinoma. Cell Metab. 29, 174–182.e5 (2019).
Saha, S. K. et al. Mutant IDH inhibits HNF-4α to block hepatocyte differentiation and promote biliary cancer. Nature 513, 110–114 (2014). This article establishes a functional relationship between IDH mutations and CCA pathogenesis, and provides a novel genetically engineered mouse model of IDH-driven malignancy.
Saha, S. K. et al. Isocitrate dehydrogenase mutations confer dasatinib hypersensitivity and SRC dependence in intrahepatic cholangiocarcinoma. Cancer Discov. 6, 727–739 (2016).
Wu, E. M. et al. Gender differences in hepatocellular cancer: disparities in nonalcoholic fatty liver disease/steatohepatitis and liver transplantation. Hepatoma Res. 4, 66 (2018).
Manieri, E. et al. Adiponectin accounts for gender differences in hepatocellular carcinoma incidence. J. Exp. Med. 216, 1108–1119 (2019).
Ma, C. et al. NAFLD causes selective CD4+ T lymphocyte loss and promotes hepatocarcinogenesis. Nature 531, 253–257 (2016). The findings from this article, for the first time, connect lipid dysregulation with decreased antitumour surveillance in CD4+ T cells.
Zhang, Q. et al. Fatty acid oxidation contributes to IL-1β secretion in M2 macrophages and promotes macrophage-mediated tumor cell migration. Mol. Immunol. 94, 27–35 (2018).
Pacella, I. et al. Fatty acid metabolism complements glycolysis in the selective regulatory T cell expansion during tumor growth. Proc. Natl Acad. Sci. USA 115, E6546–E6555 (2018).
Li, T.-E. et al. PKM2 drives hepatocellular carcinoma progression by inducing immunosuppressive microenvironment. Front. Immunol. 11, 2722 (2020).
Chen, D. P. et al. Glycolytic activation of peritumoral monocytes fosters immune privilege via the PFKFB3–PD-L1 axis in human hepatocellular carcinoma. J. Hepatol. 71, 333–343 (2019).
Klein, G. Cancer, apoptosis, and nonimmune surveillance. Cell Death Differ. 11, 13–17 (2004).
Dhar, D. et al. Liver cancer initiation requires p53 inhibition by CD44-enhanced growth factor signaling. Cancer Cell 33, 1061–1077.e6 (2018).
Tschaharganeh, D. F. et al. p53-Dependent Nestin regulation links tumor suppression to cellular plasticity in liver cancer. Cell 158, 579–592 (2014).
Kang, T. W. et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479, 547–551 (2011).
Mizukoshi, E. et al. Comparative analysis of various tumor-associated antigen-specific T-cell responses in patients with hepatocellular carcinoma. Hepatology 53, 1206–1216 (2011).
Endig, J. et al. Dual role of the adaptive immune system in liver injury and hepatocellular carcinoma development. Cancer Cell 30, 308–323 (2016).
Fu, J. et al. Impairment of CD4+ cytotoxic T cells predicts poor survival and high recurrence rates in patients with hepatocellular carcinoma. Hepatology 58, 139–149 (2013).
Garnelo, M. et al. Interaction between tumour-infiltrating B cells and T cells controls the progression of hepatocellular carcinoma. Gut 66, 342–351 (2017).
Chen, K. J. et al. Selective recruitment of regulatory T cell through CCR6–CCL20 in hepatocellular carcinoma fosters tumor progression and predicts poor prognosis. PLoS ONE 6, e24671 (2011).
Fu, J. et al. Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology 132, 2328–2339 (2007).
Gallimore, A. M. & Simon, A. K. Positive and negative influences of regulatory T cells on tumour immunity. Oncogene 27, 5886–5893 (2008).
Ghiringhelli, F., Menard, C., Martin, F. & Zitvogel, L. The role of regulatory T cells in the control of natural killer cells: relevance during tumor progression. Immunol. Rev. 214, 229–238 (2006).
Sun, Y. et al. Single-cell landscape of the ecosystem in early-relapse hepatocellular carcinoma. Cell 184, 404–421.e16 (2021). This paper uses single-cell analysis of primary and recurrent HCC tumours to produce deep insights into immune evasion mechanisms.
Dudek, M. et al. Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH. Nature 592, 444–449 (2021). This article reveals that the mechanisms behind auto-aggression by CD8+ T cells are separate from those of antigen-specific killing by CD8+ T cells.
Heinrich, B. et al. Steatohepatitis impairs T-cell-directed immunotherapies against liver tumors in mice. Gastroenterology 160, 331–345.e6 (2021).
Pfister, D. et al. NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature 592, 450–456 (2021). This paper supports stratifying patients with HCC according to their underlying aetiology, before using immunotherapy as a main or adjuvant treatment.
Albertsson, P. A. et al. NK cells and the tumour microenvironment: implications for NK-cell function and anti-tumour activity. Trends Immunol. 24, 603–609 (2003).
Bricard, G. et al. Enrichment of human CD4+ Vα24/Vβ11 invariant NKT cells in intrahepatic malignant tumors. J. Immunol. 182, 5140–5151 (2009).
Crowe, N. Y. et al. Differential antitumor immunity mediated by NKT cell subsets in vivo. J. Exp. Med. 202, 1279–1288 (2005).
Pommier, A. et al. Inflammatory monocytes are potent antitumor effectors controlled by regulatory CD4+ T cells. Proc. Natl Acad. Sci. USA 110, 13085–13090 (2013).
Lee, J. W. et al. Hepatocytes direct the formation of a pro-metastatic niche in the liver. Nature 567, 249–252 (2019).
Condeelis, J. & Pollard, J. W. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124, 263–266 (2006).
Noy, R. & Pollard, J. W. Tumor-associated macrophages: from mechanisms to therapy. Immunity 41, 49–61 (2014).
Ramachandran, P. et al. Resolving the fibrotic niche of human liver cirrhosis at single-cell level. Nature 575, 512–518 (2019).
Budhu, A. et al. Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment. Cancer Cell 10, 99–111 (2006).
Zhu, X. D. et al. High expression of macrophage colony-stimulating factor in peritumoral liver tissue is associated with poor survival after curative resection of hepatocellular carcinoma. J. Clin. Oncol. 26, 2707–2716 (2008).
Ciner, A. T., Jones, K., Muschel, R. J. & Brodt, P. The unique immune microenvironment of liver metastases: challenges and opportunities. Semin. Cancer Biol. 71, 143–156 (2021).
Yu, J. et al. Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination. Nat. Med. 27, 152–164 (2021). This paper shows that hepatic metastases utilize host peripheral tolerance mechanisms to promote CD8+ T cell depletion.
Fidler, I. J. Timeline — the pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat. Rev. Cancer 3, 453–458 (2003).
Lorentzen, A. et al. Single cell polarity in liquid phase facilitates tumour metastasis. Nat. Commun. 9, 887 (2018).
Clark, A. M., Ma, B., Taylor, D. L., Griffith, L. & Wells, A. Liver metastases: microenvironments and ex-vivo models. Exp. Biol. Med. 241, 1639–1652 (2016).
Benedicto, A., Romayor, I. & Arteta, B. Role of liver ICAM-1 in metastasis. Oncol. Lett. 14, 3883–3892 (2017).
Khatib, A. M. et al. Rapid induction of cytokine and E-selectin expression in the liver in response to metastatic tumor cells. Cancer Res. 59, 1356–1361 (1999).
Brodt, P. Role of the microenvironment in liver metastasis: from pre- to prometastatic niches. Clin. Cancer Res. 22, 5971–5982 (2016).
Wohlfeil, S. A. et al. Hepatic endothelial notch activation protects against liver metastasis by regulating endothelial-tumor cell adhesion independent of angiocrine signaling. Cancer Res. 79, 598–610 (2019).
Mendoza, L. et al. Hydrogen peroxide mediates vascular cell adhesion molecule-1 expression from interleukin-18-activated hepatic sinusoidal endothelium: implications for circulating cancer cell arrest in the murine liver. Hepatology 34, 298–310 (2001).
Hu, C. T. et al. MIF, secreted by human hepatic sinusoidal endothelial cells, promotes chemotaxis and outgrowth of colorectal cancer in liver prometastasis. Oncotarget 6, 22410–22423 (2015).
Ou, J. et al. Endothelial cell-derived fibronectin extra domain A promotes colorectal cancer metastasis via inducing epithelial–mesenchymal transition. Carcinogenesis 35, 1661–1670 (2014).
Huang, J., Pan, C., Hu, H., Zheng, S. & Ding, L. Osteopontin-enhanced hepatic metastasis of colorectal cancer cells. PLoS ONE 7, e47901 (2012).
Tabaries, S. et al. Claudin-2 promotes breast cancer liver metastasis by facilitating tumor cell interactions with hepatocytes. Mol. Cell Biol. 32, 2979–2991 (2012).
Shimizu, S. et al. Ultrastructure of early phase hepatic metastasis of human colon carcinoma cells with special reference to desmosomal junctions with hepatocytes. Pathol. Int. 50, 953–959 (2000).
Yoshioka, T. et al. Significance of integrin αvβ5 and erbB3 in enhanced cell migration and liver metastasis of colon carcinomas stimulated by hepatocyte-derived heregulin. Cancer Sci. 101, 2011–2018 (2010).
Bu, P. et al. Aldolase B-mediated fructose metabolism drives metabolic reprogramming of colon cancer liver metastasis. Cell Metab. 27, 1249–1262.e4 (2018).
Li, Y. et al. Hepatic lipids promote liver metastasis. JCI Insight 5, e136215 (2020).
Wen, S. W., Ager, E. I. & Christophi, C. Bimodal role of Kupffer cells during colorectal cancer liver metastasis. Cancer Biol. Ther. 14, 606–613 (2013).
Costa-Silva, B. et al. Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat. Cell Biol. 17, 816–826 (2015).
Hoshino, A. et al. Tumour exosome integrins determine organotropic metastasis. Nature 527, 329–335 (2015).
Shao, Y. et al. Colorectal cancer-derived small extracellular vesicles establish an inflammatory premetastatic niche in liver metastasis. Carcinogenesis 39, 1368–1379 (2018).
Bhattacharjee, S. et al. Tumor restriction by type I collagen opposes tumor-promoting effects of cancer-associated fibroblasts. J. Clin. Invest. 131, e146987 (2021).
Iredale, J. P., Thompson, A. & Henderson, N. C. Extracellular matrix degradation in liver fibrosis: biochemistry and regulation. Biochim. Biophys. Acta 1832, 876–883 (2013).
Friedman, S. L. Seminars in medicine of the Beth Israel Hospital, Boston. The cellular basis of hepatic fibrosis. Mechanisms and treatment strategies. N. Engl. J. Med. 328, 1828–1835 (1993).
Eveno, C. et al. Proof of prometastatic niche induction by hepatic stellate cells. J. Surg. Res. 194, 496–504 (2015).
Cox, D., Brennan, M. & Moran, N. Integrins as therapeutic targets: lessons and opportunities. Nat. Rev. Drug Discov. 9, 804–820 (2010).
Zhang, D. Y. & Friedman, S. L. Fibrosis-dependent mechanisms of hepatocarcinogenesis. Hepatology 56, 769–775 (2012).
Shen, Y. et al. Reduction of liver metastasis stiffness improves response to bevacizumab in metastatic colorectal cancer. Cancer Cell 37, 800–817.e7 (2020).
Zhao, W. et al. Hepatic stellate cells promote tumor progression by enhancement of immunosuppressive cells in an orthotopic liver tumor mouse model. Lab. Invest. 94, 182–191 (2014).
Hsu, B. E. et al. Immature low-density neutrophils exhibit metabolic flexibility that facilitates breast cancer liver metastasis. Cell Rep. 27, 3902–3915.e6 (2019).
Gordon-Weeks, A. N. et al. Neutrophils promote hepatic metastasis growth through fibroblast growth factor 2-dependent angiogenesis in mice. Hepatology 65, 1920–1935 (2017).
Haemmerle, M., Stone, R. L., Menter, D. G., Afshar-Kharghan, V. & Sood, A. K. The platelet lifeline to cancer: challenges and opportunities. Cancer Cell 33, 965–983 (2018).
Verheul, H. M. et al. Vascular endothelial growth factor trap blocks tumor growth, metastasis formation, and vascular leakage in an orthotopic murine renal cell cancer model. Clin. Cancer Res. 13, 4201–4208 (2007).
Gervaz, P. et al. Angiogenesis of liver metastases: role of sinusoidal endothelial cells. Dis. Colon Rectum 43, 980–986 (2000).
Kimura, Y. et al. The innate immune receptor Dectin-2 mediates the phagocytosis of cancer cells by Kupffer cells for the suppression of liver metastasis. Proc. Natl Acad. Sci. USA 113, 14097–14102 (2016).
Timmers, M. et al. Interactions between rat colon carcinoma cells and Kupffer cells during the onset of hepatic metastasis. Int. J. Cancer 112, 793–802 (2004).
Molgora, M. et al. IL-1R8 is a checkpoint in NK cells regulating anti-tumour and anti-viral activity. Nature 551, 110–114 (2017).
Takeda, K. et al. Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver natural killer cells. Nat. Med. 7, 94–100 (2001).
Ballas, Z. K., Buchta, C. M., Rosean, T. R., Heusel, J. W. & Shey, M. R. Role of NK cell subsets in organ-specific murine melanoma metastasis. PLoS ONE 8, e65599 (2013).
Ducimetière, L. et al. Conventional NK cells and tissue-resident ILC1s join forces to control liver metastasis. Proc. Natl Acad. Sci. USA 118, e2026271118 (2021).
Tauriello, D. V. F. et al. TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature 554, 538–543 (2018).
Lee, J. H. et al. Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma. Gastroenterology 148, 1383–1391.e6 (2015).
Lee, J.-H., Oh, S.-Y., Kim, J. Y. & Nishida, N. Cancer immunotherapy for hepatocellular carcinoma. Hepatoma Res. 4, 51 (2018).
Zhang, Z. et al. Gasdermin E suppresses tumour growth by activating anti-tumour immunity. Nature 579, 415–420 (2020).
Crowther, M. D. et al. Genome-wide CRISPR–Cas9 screening reveals ubiquitous T cell cancer targeting via the monomorphic MHC class I-related protein MR1. Nat. Immunol. 21, 178–185 (2020).
Sangro, B. et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J. Hepatol. 59, 81–88 (2013).
Duffy, A. G. et al. Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma. J. Hepatol. 66, 545–551 (2017).
Finn, R. S. et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N. Engl. J. Med. 382, 1894–1905 (2020). This article reports an improvement of overall survival and progression-free survival in patients with advanced unresectable HCC who were treated with atezolizumab and bevacizumab when compared with sorafenib.
Llovet, J. M. et al. Hepatocellular carcinoma. Nat. Rev. Dis. Primers 2, 16018 (2016).
El-Khoueiry, A. B. et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 389, 2492–2502 (2017).
Yarchoan, M. et al. Recent developments and therapeutic strategies against hepatocellular carcinoma. Cancer Res. 79, 4326–4330 (2019).
Harding, J. J. et al. Prospective genotyping of hepatocellular carcinoma: clinical implications of next-generation sequencing for matching patients to targeted and immune therapies. Clin. Cancer Res. 25, 2116–2126 (2019).
Jin, H. et al. A powerful drug combination strategy targeting glutamine addiction for the treatment of human liver cancer. eLife 9, e56749 (2020).
Rizvi, S. & Gores, G. J. Pathogenesis, diagnosis, and management of cholangiocarcinoma. Gastroenterology 145, 1215–1229 (2013).
Rothwell, P. M. et al. Effects of aspirin on risks of vascular events and cancer according to bodyweight and dose: analysis of individual patient data from randomised trials. Lancet 392, 387–399 (2018).
Simon, T. G. et al. Association of aspirin with hepatocellular carcinoma and liver-related mortality. N. Engl. J. Med. 382, 1018–1028 (2020).
Xiong, X. et al. Landscape of intercellular crosstalk in healthy and NASH liver revealed by single-cell secretome gene analysis. Mol. Cell 75, 644–660.e5 (2019). This article reports unprecedented insights into intercellular interaction and reprogramming of liver cells in health and disease.
Gola, A. et al. Commensal-driven immune zonation of the liver promotes host defence. Nature 589, 131–136 (2021). This paper explains the link between the localization of hepatic immune cells and host protection.
Manco, R. & Itzkovitz, S. Liver zonation. J. Hepatol. 74, 466–468 (2021).
Krenkel, O. et al. Myeloid cells in liver and bone marrow acquire a functionally distinct inflammatory phenotype during obesity-related steatohepatitis. Gut 69, 551–563 (2020).
MacParland, S. A. et al. Single cell RNA sequencing of human liver reveals distinct intrahepatic macrophage populations. Nat. Commun. 9, 4383 (2018).
Dobie, R. et al. Single-cell transcriptomics uncovers zonation of function in the mesenchyme during liver fibrosis. Cell Rep. 29, 1832–1847.e8 (2019).
Verfaillie, T. et al. PERK is required at the ER–mitochondrial contact sites to convey apoptosis after ROS-based ER stress. Cell Death Differ. 19, 1880–1891 (2012).
Liu, J. et al. Endoplasmic reticulum stress modulates liver inflammatory immune response in the pathogenesis of liver ischemia and reperfusion injury. Transplantation 94, 211–217 (2012).
Ren, F. et al. Endoplasmic reticulum stress-activated glycogen synthase kinase 3β aggravates liver inflammation and hepatotoxicity in mice with acute liver failure. Inflammation 38, 1151–1165 (2015).
Wei, C. et al. Tumor microenvironment regulation by the endoplasmic reticulum stress transmission mediator Golgi protein 73 in mice. Hepatology 70, 851–870 (2019).
Enzan, H. et al. α-Smooth muscle actin-positive perisinusoidal stromal cells in human hepatocellular carcinoma. Hepatology 19, 895–903 (1994).
Seitz, H. K. & Stickel, F. Risk factors and mechanisms of hepatocarcinogenesis with special emphasis on alcohol and oxidative stress. Biol. Chem. 387, 349–360 (2006).
Heindryckx, F., Colle, I. & Van Vlierberghe, H. Experimental mouse models for hepatocellular carcinoma research. Int. J. Exp. Pathol. 90, 367–386 (2009).
Carloni, V., Luong, T. V. & Rombouts, K. Hepatic stellate cells and extracellular matrix in hepatocellular carcinoma: more complicated than ever. Liver Int. 34, 834–843 (2014).
Baglieri, J., Brenner, D. A. & Kisseleva, T. The role of fibrosis and liver-associated fibroblasts in the pathogenesis of hepatocellular carcinoma. Int. J. Mol. Sci. 20, 1723 (2019).
Rosenberg, W. M. et al. Serum markers detect the presence of liver fibrosis: a cohort study. Gastroenterology 127, 1704–1713 (2004).
Wu, Y., Qiao, X., Qiao, S. & Yu, L. Targeting integrins in hepatocellular carcinoma. Expert. Opin. Ther. Targets 15, 421–437 (2011).
Dhar, D., Baglieri, J., Kisseleva, T. & Brenner, D. A. Mechanisms of liver fibrosis and its role in liver cancer. Exp. Biol. Med. 245, 96–108 (2020).
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).
The authors declare no competing interests.
Peer review information
Nature Reviews Cancer thanks J. Fan, J. Moscat and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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.
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.
Rights and permissions
About this article
Cite this article
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
This article is cited by
Macrophage-Derived MMP-9 and MMP-2 are Closely Related to the Rupture of the Fibrous Capsule of Hepatocellular Carcinoma Leading to Tumor Invasion
Biological Procedures Online (2023)
Advances in the clinical management of uveal melanoma
Nature Reviews Clinical Oncology (2023)
AADAC protects colorectal cancer liver colonization from ferroptosis through SLC7A11-dependent inhibition of lipid peroxidation
Journal of Experimental & Clinical Cancer Research (2022)
The evolving view of thermogenic fat and its implications in cancer and metabolic diseases
Signal Transduction and Targeted Therapy (2022)
Overcoming biophysical barriers with innovative therapeutic delivery approaches
Cancer Gene Therapy (2022)