Hepatic Stellate Cells Functional Heterogeneity in Liver Cancer

Laura Sererols-Viñas; Gemma Garcia-Vicién; Paloma Ruiz-Blázquez; Ting-Fang Lee; Youngmin A. Lee; Ester Gonzalez-Sanchez; Javier Vaquero; Anna Moles; Aveline Filliol; Silvia Affò

doi:10.1055/a-2551-0724

Seminars in Liver Disease, Inhaltsverzeichnis

Semin Liver Dis 2025; 45(01): 033-051
DOI: 10.1055/a-2551-0724

Review Article

Hepatic Stellate Cells Functional Heterogeneity in Liver Cancer

Laura Sererols-Viñas^*

¹Tumor Microenvironment Plasticity and Heterogeneity Research Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

²University of Barcelona, Barcelona, Spain

,

Gemma Garcia-Vicién^*

¹Tumor Microenvironment Plasticity and Heterogeneity Research Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

,

Paloma Ruiz-Blázquez

²University of Barcelona, Barcelona, Spain

³Tissue Remodeling Fibrosis and Cancer Group, Institute of Biomedical Research of Barcelona, Spanish National Research Council, Barcelona, Spain

⁴Institute of Biomedical Research of Barcelona (IDIBAPS), Barcelona, Spain

⁵CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Madrid, Spain

,

Ting-Fang Lee

⁶Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee

,

Youngmin A. Lee

⁶Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee

,

Ester Gonzalez-Sanchez

⁷HepatoBiliary Tumours Lab, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, CSIC-Universidad de Salamanca, Salamanca, Spain

⁸Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain

,

Javier Vaquero

⁵CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Madrid, Spain

⁷HepatoBiliary Tumours Lab, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, CSIC-Universidad de Salamanca, Salamanca, Spain

⁹TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain

,

Anna Moles

³Tissue Remodeling Fibrosis and Cancer Group, Institute of Biomedical Research of Barcelona, Spanish National Research Council, Barcelona, Spain

⁴Institute of Biomedical Research of Barcelona (IDIBAPS), Barcelona, Spain

⁵CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Madrid, Spain

,

Aveline Filliol^#

¹⁰Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York

,

Silvia Affò^#

¹Tumor Microenvironment Plasticity and Heterogeneity Research Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

› Institutsangaben

Abstract

Hepatic stellate cells (HSCs) are the liver's pericytes, and play key roles in liver homeostasis, regeneration, fibrosis, and cancer. Upon injury, HSCs activate and are the main origin of myofibroblasts and cancer-associated fibroblasts (CAFs) in liver fibrosis and cancer. Primary liver cancer has a grim prognosis, ranking as the third leading cause of cancer-related deaths worldwide, with hepatocellular carcinoma (HCC) being the predominant type, followed by intrahepatic cholangiocarcinoma (iCCA). Moreover, the liver hosts 35% of all metastatic lesions. The distinct spatial distribution and functional roles of HSCs across these malignancies represent a significant challenge for universal therapeutic strategies, requiring a nuanced and tailored understanding of their contributions. This review examines the heterogeneous roles of HSCs in liver cancer, focusing on their spatial localization, dynamic interactions within the tumor microenvironment (TME), and emerging therapeutic opportunities, including strategies to modulate their activity, and harness their potential as targets for antifibrotic and antitumor interventions.

Keywords

hepatic stellate cells - liver cancer - cancer-associated fibroblasts - tumor microenvironment

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References
1 Sung H, Ferlay J, Siegel RL. et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71 (03) 209-249
2 Banales JM, Marin JJG, Lamarca A. et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol 2020; 17 (09) 557-588
3 Martin J, Petrillo A, Smyth EC. et al. Colorectal liver metastases: current management and future perspectives. World J Clin Oncol 2020; 11 (10) 761-808
4 Bojmar L, Zambirinis CP, Hernandez JM. et al. Multi-parametric atlas of the pre-metastatic liver for prediction of metastatic outcome in early-stage pancreatic cancer. Nat Med 2024; 30 (08) 2170-2180
5 Affo S, Yu LX, Schwabe RF. The role of cancer-associated fibroblasts and fibrosis in liver cancer. Annu Rev Pathol 2017; 12: 153-186
6 Collaborators GUHD. GBD US Health Disparities Collaborators. Burden of liver cancer mortality by county, race, and ethnicity in the USA, 2000-19: a systematic analysis of health disparities. Lancet Public Health 2024; 9 (03) e186-e198
7 Younossi Z, Stepanova M, Ong JP. et al; Global Nonalcoholic Steatohepatitis Council. Nonalcoholic steatohepatitis is the fastest growing cause of hepatocellular carcinoma in liver transplant candidates. Clin Gastroenterol Hepatol 2019; 17 (04) 748-755.e3
8 Huang DQ, El-Serag HB, Loomba R. Global epidemiology of NAFLD-related HCC: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol 2021; 18 (04) 223-238
9 Kamm DR, McCommis KS. Hepatic stellate cells in physiology and pathology. J Physiol 2022; 600 (08) 1825-1837
10 Friedman SL. Evolving challenges in hepatic fibrosis. Nat Rev Gastroenterol Hepatol 2010; 7 (08) 425-436
11 Hernandez-Gea V, Friedman SL. Pathogenesis of liver fibrosis. Annu Rev Pathol 2011; 6: 425-456
12 Ying F, Chan MSM, Lee TKW. Cancer-associated fibroblasts in hepatocellular carcinoma and cholangiocarcinoma. Cell Mol Gastroenterol Hepatol 2023; 15 (04) 985-999
13 Filliol A, Saito Y, Nair A. et al. Opposing roles of hepatic stellate cell subpopulations in hepatocarcinogenesis. Nature 2022; 610 (7931) 356-365
14 Cogliati B, Yashaswini CN, Wang S, Sia D, Friedman SL. Friend or foe? The elusive role of hepatic stellate cells in liver cancer. Nat Rev Gastroenterol Hepatol 2023; 20 (10) 647-661
15 Giampieri MP, Jezequel AM, Orlandi F. The lipocytes in normal human liver. A quantitative study. Digestion 1981; 22 (04) 165-169
16 Asahina K, Tsai SY, Li P. et al. Mesenchymal origin of hepatic stellate cells, submesothelial cells, and perivascular mesenchymal cells during mouse liver development. Hepatology 2009; 49 (03) 998-1011
17 D'Ambrosio DN, Walewski JL, Clugston RD, Berk PD, Rippe RA, Blaner WS. Distinct populations of hepatic stellate cells in the mouse liver have different capacities for retinoid and lipid storage. PLoS One 2011; 6 (09) e24993
18 Mederacke I, Hsu CC, Troeger JS. et al. Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nat Commun 2013; 4: 2823
19 Merens V, Knetemann E, Gürbüz E. et al. Hepatic stellate cell single cell atlas reveals a highly similar activation process across liver disease aetiologies. JHEP Rep Innov Hepatol 2024; 101223: 2589-5559
20 Asahina K, Zhou B, Pu WT, Tsukamoto H. Septum transversum-derived mesothelium gives rise to hepatic stellate cells and perivascular mesenchymal cells in developing mouse liver. Hepatology 2011; 53 (03) 983-995
21 Dobie R, Wilson-Kanamori JR, Henderson BEP. et al. Single-cell transcriptomics uncovers zonation of function in the mesenchyme during liver fibrosis. Cell Rep 2019; 29 (07) 1832-1847.e8
22 Payen VL, Lavergne A, Alevra Sarika N. et al. Single-cell RNA sequencing of human liver reveals hepatic stellate cell heterogeneity. JHEP Rep Innov Hepatol 2021; 3 (03) 100278
23 Blaner WS, O'Byrne SM, Wongsiriroj N. et al. Hepatic stellate cell lipid droplets: a specialized lipid droplet for retinoid storage. Biochim Biophys Acta 2009; 1791 (06) 467-473
24 Friedman SL. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev 2008; 88 (01) 125-172
25 Wang S, Li K, Pickholz E. et al. An autocrine signaling circuit in hepatic stellate cells underlies advanced fibrosis in nonalcoholic steatohepatitis. Sci Transl Med 2023; 15 (677) eadd3949
26 Deleve LD, Wang X, Guo Y. Sinusoidal endothelial cells prevent rat stellate cell activation and promote reversion to quiescence. Hepatology 2008; 48 (03) 920-930
27 Stewart RK, Dangi A, Huang C. et al. A novel mouse model of depletion of stellate cells clarifies their role in ischemia/reperfusion- and endotoxin-induced acute liver injury. J Hepatol 2014; 60 (02) 298-305
28 Trinh VQ, Lee TF, Lemoinne S. et al. Hepatic stellate cells maintain liver homeostasis through paracrine neurotrophin-3 signaling that induces hepatocyte proliferation. Sci Signal 2023; 16 (787) eadf6696
29 Tsuchida T, Friedman SL. Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol 2017; 14 (07) 397-411
30 Lemoinne S, Cadoret A, El Mourabit H, Thabut D, Housset C. Origins and functions of liver myofibroblasts. Biochim Biophys Acta 2013; 1832 (07) 948-954
31 Kisseleva T, Brenner DA. Hepatic stellate cells and the reversal of fibrosis. J Gastroenterol Hepatol 2006; 21 (Suppl. 03) S84-S87
32 Iwaisako K, Jiang C, Zhang M. et al. Origin of myofibroblasts in the fibrotic liver in mice. Proc Natl Acad Sci U S A 2014; 111 (32) E3297-E3305
33 Khan MA, Fischer J, Harrer L, Schwiering F, Groneberg D, Friebe A. Hepatic stellate cells in zone 1 engage in capillarization rather than myofibroblast formation in murine liver fibrosis. Sci Rep 2024; 14 (01) 18840
34 Xu J, Kisseleva T. Bone marrow-derived fibrocytes contribute to liver fibrosis. Exp Biol Med (Maywood) 2015; 240 (06) 691-700
35 Yang W, He H, Wang T. et al. Single-cell transcriptomic analysis reveals a hepatic stellate cell-activation roadmap and myofibroblast origin during liver fibrosis in mice. Hepatology 2021; 74 (05) 2774-2790
36 Ramachandran P, Dobie R, Wilson-Kanamori JR. et al. Resolving the fibrotic niche of human liver cirrhosis at single-cell level. Nature 2019; 575 (7783) 512-518
37 Bogomolova A, Balakrishnan A, Ott M, Sharma AD. “The good, the bad, and the ugly”—about diverse phenotypes of hepatic stellate cells in the liver. Cell Mol Gastroenterol Hepatol 2024; 17 (04) 607-622
38 Troeger JS, Mederacke I, Gwak GY. et al. Deactivation of hepatic stellate cells during liver fibrosis resolution in mice. Gastroenterology 2012; 143 (04) 1073-83.e22
39 Tacke F, Trautwein C. Mechanisms of liver fibrosis resolution. J Hepatol 2015; 63 (04) 1038-1039
40 Kisseleva T, Cong M, Paik Y. et al. Myofibroblasts revert to an inactive phenotype during regression of liver fibrosis. Proc Natl Acad Sci U S A 2012; 109 (24) 9448-9453
41 Iredale JP, Benyon RC, Pickering J. et al. Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors. J Clin Invest 1998; 102 (03) 538-549
42 Krizhanovsky V, Yon M, Dickins RA. et al. Senescence of activated stellate cells limits liver fibrosis. Cell 2008; 134 (04) 657-667
43 Takahashi A, Loo TM, Okada R. et al. Downregulation of cytoplasmic DNases is implicated in cytoplasmic DNA accumulation and SASP in senescent cells. Nat Commun 2018; 9 (01) 1249
44 Burton DG, Krizhanovsky V. Physiological and pathological consequences of cellular senescence. Cell Mol Life Sci 2014; 71 (22) 4373-4386
45 Yashaswini CN, Qin T, Bhattacharya D. et al. Phenotypes and ontogeny of senescent hepatic stellate cells in metabolic dysfunction-associated steatohepatitis. J Hepatol 2024; 81 (02) 207-217
46 Yoshimoto S, Loo TM, Atarashi K. et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 2013; 499 (7456) 97-101
47 Lujambio A, Akkari L, Simon J. et al. Non-cell-autonomous tumor suppression by p53. Cell 2013; 153 (02) 449-460
48 Amor C, Feucht J, Leibold J. et al. Senolytic CAR T cells reverse senescence-associated pathologies. Nature 2020; 583 (7814) 127-132
49 Li F, Huangyang P, Burrows M. et al. FBP1 loss disrupts liver metabolism and promotes tumorigenesis through a hepatic stellate cell senescence secretome. Nat Cell Biol 2020; 22 (06) 728-739
50 Llovet JM, Kelley RK, Villanueva A. et al. Hepatocellular carcinoma. Nat Rev Dis Primers 2021; 7 (01) 6
51 Otto J, Verwaayen A, Penners C. et al. Expression of Cyclin E1 in hepatic stellate cells is critical for the induction and progression of liver fibrosis and hepatocellular carcinoma in mice. Cell Death Dis 2023; 14 (08) 549
52 Goodman ZD. Neoplasms of the liver. Mod Pathol 2007; 20 (Suppl. 01) S49-S60
53 Ji J, Eggert T, Budhu A. et al. Hepatic stellate cell and monocyte interaction contributes to poor prognosis in hepatocellular carcinoma. Hepatology 2015; 62 (02) 481-495
54 Salomao M, Yu WM, Brown Jr RS, Emond JC, Lefkowitch JH. Steatohepatitic hepatocellular carcinoma (SH-HCC): a distinctive histological variant of HCC in hepatitis C virus-related cirrhosis with associated NAFLD/NASH. Am J Surg Pathol 2010; 34 (11) 1630-1636
55 Lau EY, Lo J, Cheng BY. et al. Cancer-associated fibroblasts regulate tumor-initiating cell plasticity in hepatocellular carcinoma through c-Met/FRA1/HEY1 signaling. Cell Rep 2016; 15 (06) 1175-1189
56 Fang M, Yuan J, Chen M. et al. The heterogenic tumor microenvironment of hepatocellular carcinoma and prognostic analysis based on tumor neo-vessels, macrophages and α-SMA. Oncol Lett 2018; 15 (04) 4805-4812
57 Roy AM, Iyer R, Chakraborty S. The extracellular matrix in hepatocellular carcinoma: mechanisms and therapeutic vulnerability. Cell Rep Med 2023; 4 (09) 101170
58 Arteel GE. Hepatic extracellular matrix and its role in the regulation of liver phenotype. Semin Liver Dis 2024; 44 (03) 343-355
59 Masuzaki R, Tateishi R, Yoshida H. et al. Prospective risk assessment for hepatocellular carcinoma development in patients with chronic hepatitis C by transient elastography. Hepatology 2009; 49 (06) 1954-1961
60 Poynard T, Vergniol J, Ngo Y. et al; FibroFrance Study Group, Epic3 Study Group, Bordeaux HCV Study Group. Staging chronic hepatitis C in seven categories using fibrosis biomarker (FibroTest™) and transient elastography (FibroScan®). J Hepatol 2014; 60 (04) 706-714
61 Wang HM, Hung CH, Lu SN. et al. Liver stiffness measurement as an alternative to fibrotic stage in risk assessment of hepatocellular carcinoma incidence for chronic hepatitis C patients. Liver Int 2013; 33 (05) 756-761
62 Pan CQ, Park AJ, Park JS. New perspectives in hepatocellular carcinoma surveillance after hepatitis C virus eradication. Gastroenterol Rep (Oxf) 2024; 12: goae085
63 Arriazu E, Ruiz de Galarreta M, Cubero FJ. et al. Extracellular matrix and liver disease. Antioxid Redox Signal 2014; 21 (07) 1078-1097
64 Nault JC, Calderaro J, Di Tommaso L. et al. Telomerase reverse transcriptase promoter mutation is an early somatic genetic alteration in the transformation of premalignant nodules in hepatocellular carcinoma on cirrhosis. Hepatology 2014; 60 (06) 1983-1992
65 Nault JC, Mallet M, Pilati C. et al. High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions. Nat Commun 2013; 4: 2218
66 Saito Y, Yin D, Kubota N. et al. A therapeutically targetable TAZ-TEAD2 pathway drives the growth of hepatocellular carcinoma via ANLN and KIF23. Gastroenterology 2023; 164 (07) 1279-1292
67 Dolin CE, Arteel GE. The matrisome, inflammation, and liver disease. Semin Liver Dis 2020; 40 (02) 180-188
68 Stoker MG, Shearer M, O'Neill C. Growth inhibition of polyoma-transformed cells by contact with static normal fibroblasts. J Cell Sci 1966; 1 (03) 297-310
69 Alkasalias T, Flaberg E, Kashuba V. et al. Inhibition of tumor cell proliferation and motility by fibroblasts is both contact and soluble factor dependent. Proc Natl Acad Sci U S A 2014; 111 (48) 17188-17193
70 Zhou L, Yang K, Randall Wickett R, Zhang Y. Dermal fibroblasts induce cell cycle arrest and block epithelial-mesenchymal transition to inhibit the early stage melanoma development. Cancer Med 2016; 5 (07) 1566-1579
71 Chou HS, Hsieh CC, Yang HR. et al. Hepatic stellate cells regulate immune response by way of induction of myeloid suppressor cells in mice. Hepatology 2011; 53 (03) 1007-1019
72 Langhans B, Krämer B, Louis M. et al. Intrahepatic IL-8 producing Foxp3⁺CD4⁺ regulatory T cells and fibrogenesis in chronic hepatitis C. J Hepatol 2013; 59 (02) 229-235
73 Dunham RM, Thapa M, Velazquez VM. et al. Hepatic stellate cells preferentially induce Foxp3+ regulatory T cells by production of retinoic acid. J Immunol 2013; 190 (05) 2009-2016
74 Zhao W, Su W, Kuang P. et al. The role of hepatic stellate cells in the regulation of T-cell function and the promotion of hepatocellular carcinoma. Int J Oncol 2012; 41 (02) 457-464
75 Dangi A, Sumpter TL, Kimura S. et al. Selective expansion of allogeneic regulatory T cells by hepatic stellate cells: role of endotoxin and implications for allograft tolerance. J Immunol 2012; 188 (08) 3667-3677
76 Charles R, Chou HS, Wang L, Fung JJ, Lu L, Qian S. Human hepatic stellate cells inhibit T-cell response through B7-H1 pathway. Transplantation 2013; 96 (01) 17-24
77 Yu MC, Chen CH, Liang X. et al. Inhibition of T-cell responses by hepatic stellate cells via B7-H1-mediated T-cell apoptosis in mice. Hepatology 2004; 40 (06) 1312-1321
78 Xia Y, Chen R, Ye SL, Sun R, Chen J, Zhao Y. Inhibition of T-cell responses by intratumoral hepatic stellate cells contribute to migration and invasion of hepatocellular carcinoma. Clin Exp Metastasis 2011; 28 (07) 661-674
79 Xia YH, Wang ZM, Chen RX. et al. T-cell apoptosis induced by intratumoral activated hepatic stellate cells is associated with lung metastasis in hepatocellular carcinoma. Oncol Rep 2013; 30 (03) 1175-1184
80 Zhao W, Zhang L, Yin Z. et al. Activated hepatic stellate cells promote hepatocellular carcinoma development in immunocompetent mice. Int J Cancer 2011; 129 (11) 2651-2661
81 Li T, Yang Y, Hua X. et al. Hepatocellular carcinoma-associated fibroblasts trigger NK cell dysfunction via PGE2 and IDO. Cancer Lett 2012; 318 (02) 154-161
82 Shi J, Zhao J, Zhang X. et al. Activated hepatic stellate cells impair NK cell anti-fibrosis capacity through a TGF-β-dependent emperipolesis in HBV cirrhotic patients. Sci Rep 2017; 7: 44544
83 Katz JB, Muller AJ, Prendergast GC. Indoleamine 2,3-dioxygenase in T-cell tolerance and tumoral immune escape. Immunol Rev 2008; 222: 206-221
84 Becker JC, Andersen MH, Schrama D, Thor Straten P. Immune-suppressive properties of the tumor microenvironment. Cancer Immunol Immunother 2013; 62 (07) 1137-1148
85 Xi S, Zheng X, Li X. et al. Activated hepatic stellate cells induce infiltration and formation of CD163⁺ macrophages via CCL2/CCR2 pathway. Front Med (Lausanne) 2021; 8: 627927
86 Pradere JP, Kluwe J, De Minicis S. et al. Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice. Hepatology 2013; 58 (04) 1461-1473
87 Savage TM, Fortson KT, de Los Santos-Alexis K. et al. Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis. Immunity 2024; 57 (02) 303-318.e6
88 Giannelli G, Koudelkova P, Dituri F, Mikulits W. Role of epithelial to mesenchymal transition in hepatocellular carcinoma. J Hepatol 2016; 65 (04) 798-808
89 Ravi R, Noonan KA, Pham V. et al. Bifunctional immune checkpoint-targeted antibody-ligand traps that simultaneously disable TGFβ enhance the efficacy of cancer immunotherapy. Nat Commun 2018; 9 (01) 741
90 DeLeve LD. Liver sinusoidal endothelial cells in hepatic fibrosis. Hepatology 2015; 61 (05) 1740-1746
91 Xie G, Wang X, Wang L. et al. Role of differentiation of liver sinusoidal endothelial cells in progression and regression of hepatic fibrosis in rats. Gastroenterology 2012; 142 (04) 918-927.e6
92 Liu L, You Z, Yu H. et al. Mechanotransduction-modulated fibrotic microniches reveal the contribution of angiogenesis in liver fibrosis. Nat Mater 2017; 16 (12) 1252-1261
93 Chen JA, Shi M, Li JQ, Qian CN. Angiogenesis: multiple masks in hepatocellular carcinoma and liver regeneration. Hepatol Int 2010; 4 (03) 537-547
94 Lin N, Chen Z, Lu Y, Li Y, Hu K, Xu R. Role of activated hepatic stellate cells in proliferation and metastasis of hepatocellular carcinoma. Hepatol Res 2015; 45 (03) 326-336
95 Lefere S, Van de Velde F, Hoorens A. et al. Angiopoietin-2 promotes pathological angiogenesis and is a therapeutic target in murine nonalcoholic fatty liver disease. Hepatology 2019; 69 (03) 1087-1104
96 Kudo M, Ren Z, Guo Y. et al; LEAP-012 investigators. Transarterial chemoembolisation combined with lenvatinib plus pembrolizumab versus dual placebo for unresectable, non-metastatic hepatocellular carcinoma (LEAP-012): a multicentre, randomised, double-blind, phase 3 study. Lancet 2025; 405 (10474): 203-215
97 Finn RS, Qin S, Ikeda M. et al; IMbrave150 Investigators. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med 2020; 382 (20) 1894-1905
98 European Association for the Study of the Liver. Management of hepatocellular carcinoma. J Hepatol 2018; 69 (01) 182-236
99 Affo S, Filliol A, Gores GJ, Schwabe RF. Fibroblasts in liver cancer: functions and therapeutic translation. Lancet Gastroenterol Hepatol 2023; 8 (08) 748-759
100 Llovet JM, Montal R, Sia D, Finn RS. Molecular therapies and precision medicine for hepatocellular carcinoma. Nat Rev Clin Oncol 2018; 15 (10) 599-616
101 Désert R, Mebarki S, Desille M. et al. “Fibrous nests” in human hepatocellular carcinoma express a Wnt-induced gene signature associated with poor clinical outcome. Int J Biochem Cell Biol 2016; 81 (Pt A): 195-207
102 Desert R, Chen W, Ge X. et al. Hepatocellular carcinomas, exhibiting intratumor fibrosis, express cancer-specific extracellular matrix remodeling and WNT/TGFB signatures, associated with poor outcome. Hepatology 2023; 78 (03) 741-757
103 Li Z, Pai R, Gupta S. et al. Presence of onco-fetal neighborhoods in hepatocellular carcinoma is associated with relapse and response to immunotherapy. Nat Cancer 2024; 5 (01) 167-186
104 Xue R, Zhang Q, Cao Q. et al. Liver tumour immune microenvironment subtypes and neutrophil heterogeneity. Nature 2022; 612 (7938) 141-147
105 Zhu AX, Abbas AR, de Galarreta MR. et al. Molecular correlates of clinical response and resistance to atezolizumab in combination with bevacizumab in advanced hepatocellular carcinoma. Nat Med 2022; 28 (08) 1599-1611
106 Qiu X, Zhou T, Li S. et al. Spatial single-cell protein landscape reveals vimentin^high macrophages as immune-suppressive in the microenvironment of hepatocellular carcinoma. Nat Cancer 2024; 5 (10) 1557-1578
107 Liu Y, Xun Z, Ma K. et al. Identification of a tumour immune barrier in the HCC microenvironment that determines the efficacy of immunotherapy. J Hepatol 2023; 78 (04) 770-782
108 Bruni S, Mercogliano MF, Mauro FL, Cordo Russo RI, Schillaci R. Cancer immune exclusion: breaking the barricade for a successful immunotherapy. Front Oncol 2023; 13: 1135456
109 Zhang S, Yuan L, Danilova L. et al. Spatial transcriptomics analysis of neoadjuvant cabozantinib and nivolumab in advanced hepatocellular carcinoma identifies independent mechanisms of resistance and recurrence. Genome Med 2023; 15 (01) 72
110 Bagaev A, Kotlov N, Nomie K. et al. Conserved pan-cancer microenvironment subtypes predict response to immunotherapy. Cancer Cell 2021; 39 (06) 845-865.e7
111 Murai H, Kodama T, Maesaka K. et al. Multiomics identifies the link between intratumor steatosis and the exhausted tumor immune microenvironment in hepatocellular carcinoma. Hepatology 2023; 77 (01) 77-91
112 Sun X, Wu B, Chiang HC. et al. Tumour DDR1 promotes collagen fibre alignment to instigate immune exclusion. Nature 2021; 599 (7886) 673-678
113 Baglieri J, Zhang C, Liang S. et al. Nondegradable collagen increases liver fibrosis but not hepatocellular carcinoma in mice. Am J Pathol 2021; 191 (09) 1564-1579
114 Xiong YX, Zhang XC, Zhu JH. et al. Collagen I-DDR1 signaling promotes hepatocellular carcinoma cell stemness via Hippo signaling repression. Cell Death Differ 2023; 30 (07) 1648-1665
115 Su H, Yang F, Fu R. et al. Collagenolysis-dependent DDR1 signalling dictates pancreatic cancer outcome. Nature 2022; 610 (7931) 366-372
116 Filliol A, Schwabe RF. Contributions of fibroblasts, extracellular matrix, stiffness, and mechanosensing to hepatocarcinogenesis. Semin Liver Dis 2019; 39 (03) 315-333
117 Affo S, Nair A, Brundu F. et al. Promotion of cholangiocarcinoma growth by diverse cancer-associated fibroblast subpopulations. Cancer Cell 2021; 39 (06) 866-882.e11
118 Bhattacharjee S, Hamberger F, Ravichandra A. et al. Tumor restriction by type I collagen opposes tumor-promoting effects of cancer-associated fibroblasts. J Clin Invest 2021; 131 (11) 131
119 Tan HX, Gong WZ, Zhou K. et al. CXCR4/TGF-β1 mediated hepatic stellate cells differentiation into carcinoma-associated fibroblasts and promoted liver metastasis of colon cancer. Cancer Biol Ther 2020; 21 (03) 258-268
120 Brivio S, Cadamuro M, Strazzabosco M, Fabris L. Tumor reactive stroma in cholangiocarcinoma: the fuel behind cancer aggressiveness. World J Hepatol 2017; 9 (09) 455-468
121 Piersma B, Hayward MK, Weaver VM. Fibrosis and cancer: a strained relationship. Biochim Biophys Acta Rev Cancer 2020; 1873 (02) 188356
122 Latacz E, Höppener D, Bohlok A. et al. Histopathological growth patterns of liver metastasis: updated consensus guidelines for pattern scoring, perspectives and recent mechanistic insights. Br J Cancer 2022; 127 (06) 988-1013
123 Ravichandra A, Bhattacharjee S, Affò S. Cancer-associated fibroblasts in intrahepatic cholangiocarcinoma progression and therapeutic resistance. Adv Cancer Res 2022; 156: 201-226
124 Cantallops Vilà P, Ravichandra A, Agirre Lizaso A, Perugorria MJ, Affò S. Heterogeneity, crosstalk, and targeting of cancer-associated fibroblasts in cholangiocarcinoma. Hepatology 2024; 79 (04) 941-958
125 Mertens JC, Fingas CD, Christensen JD. et al. Therapeutic effects of deleting cancer-associated fibroblasts in cholangiocarcinoma. Cancer Res 2013; 73 (02) 897-907
126 Lan C, Kitano Y, Yamashita YI. et al. Cancer-associated fibroblast senescence and its relation with tumour-infiltrating lymphocytes and PD-L1 expressions in intrahepatic cholangiocarcinoma. Br J Cancer 2022; 126 (02) 219-227
127 Özdemir BC, Pentcheva-Hoang T, Carstens JL. et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 2014; 25 (06) 719-734
128 Nagtegaal ID, Odze RD, Klimstra D. et al; WHO Classification of Tumours Editorial Board. The 2019 WHO classification of tumours of the digestive system. Histopathology 2020; 76 (02) 182-188
129 Akita M, Fujikura K, Ajiki T. et al. Dichotomy in intrahepatic cholangiocarcinomas based on histologic similarities to hilar cholangiocarcinomas. Mod Pathol 2017; 30 (07) 986-997
130 Chung T, Rhee H, Nahm JH. et al. Clinicopathological characteristics of intrahepatic cholangiocarcinoma according to gross morphologic type: cholangiolocellular differentiation traits and inflammation- and proliferation-phenotypes. HPB (Oxford) 2020; 22 (06) 864-873
131 Fernández Moro C, Geyer N, Harrizi S. et al. An idiosyncratic zonated stroma encapsulates desmoplastic liver metastases and originates from injured liver. Nat Commun 2023; 14 (01) 5024
132 Li Z, Nguyen Canh H, Takahashi K. et al. Histopathological growth pattern and vessel co-option in intrahepatic cholangiocarcinoma. Med Mol Morphol 2024; 57 (03) 200-217
133 Garcia-Vicién G, Mezheyeuski A, Bañuls M, Ruiz-Roig N, Molleví DG. The tumor microenvironment in liver metastases from colorectal carcinoma in the context of the histologic growth patterns. Int J Mol Sci 2021; 22 (04) 22
134 Garcia-Vicién G, Mezheyeuski A, Micke P. et al. Spatial immunology in liver metastases from colorectal carcinoma according to the histologic growth pattern. Cancers (Basel) 2022; 14 (03) 14
135 Garcia-Vicién G, Ruiz N, Micke P. et al. The histological growth patterns in liver metastases from colorectal cancer display differences in lymphoid, myeloid, and mesenchymal cells. MedComm 2024; 5 (12) e70000
136 Affò S, Sererols-Vinas L, Garcia-Vicién G. et al. Cancer-associated fibroblasts in intrahepatic cholangiocarcinoma: insights into origins, heterogeneity, lymphangiogenesis, and peritoneal metastasis. Am J Pathol 2025; 195 (03) 378-396
137 Zhang M, Yang H, Wan L. et al. Single-cell transcriptomic architecture and intercellular crosstalk of human intrahepatic cholangiocarcinoma. J Hepatol 2020; 73 (05) 1118-1130
138 Martin-Serrano MA, Kepecs B, Torres-Martin M. et al. Novel microenvironment-based classification of intrahepatic cholangiocarcinoma with therapeutic implications. Gut 2023; 72 (04) 736-748
139 Chen Y, Kim J, Yang S. et al. Type I collagen deletion in αSMA⁺ myofibroblasts augments immune suppression and accelerates progression of pancreatic cancer. Cancer Cell 2021; 39 (04) 548-565.e6
140 Yang YM, Kim J, Wang Z. et al. Metastatic tumor growth in steatotic liver is promoted by HAS2-mediated fibrotic tumor microenvironment. J Clin Invest 2025; e180802 . Epub ahead of print
141 Giraldez MD, Carneros D, Garbers C, Rose-John S, Bustos M. New insights into IL-6 family cytokines in metabolism, hepatology and gastroenterology. Nat Rev Gastroenterol Hepatol 2021; 18 (11) 787-803
142 Xiong S, Wang R, Chen Q. et al. Cancer-associated fibroblasts promote stem cell-like properties of hepatocellular carcinoma cells through IL-6/STAT3/Notch signaling. Am J Cancer Res 2018; 8 (02) 302-316
143 Li X, Wang Z, Jiao C. et al. Hepatocyte SGK1 activated by hepatic ischemia-reperfusion promotes the recurrence of liver metastasis via IL-6/STAT3. J Transl Med 2023; 21 (01) 121
144 Huang B, Lang X, Li X. The role of IL-6/JAK2/STAT3 signaling pathway in cancers. Front Oncol 2022; 12: 1023177
145 Johnson DE, O'Keefe RA, Grandis JR. Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat Rev Clin Oncol 2018; 15 (04) 234-248
146 Ezhilarasan D, Najimi M. Deciphering the possible reciprocal loop between hepatic stellate cells and cancer cells in the tumor microenvironment of the liver. Crit Rev Oncol Hematol 2023; 182: 103902
147 Montori M, Scorzoni C, Argenziano ME. et al. Cancer-associated fibroblasts in cholangiocarcinoma: current knowledge and possible implications for therapy. J Clin Med 2022; 11 (21) 11
148 Fabris L, Cadamuro M, Cagnin S, Strazzabosco M, Gores GJ. Liver matrix in benign and malignant biliary tract disease. Semin Liver Dis 2020; 40 (03) 282-297
149 Zeng J, Liu Z, Sun S. et al. Tumor-associated macrophages recruited by periostin in intrahepatic cholangiocarcinoma stem cells. Oncol Lett 2018; 15 (06) 8681-8686
150 Lowy CM, Oskarsson T. Tenascin C in metastasis: a view from the invasive front. Cell Adh Migr 2015; 9 (1-2): 112-124
151 Levental KR, Yu H, Kass L. et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 2009; 139 (05) 891-906
152 Barbazán J, Matic Vignjevic D. Cancer associated fibroblasts: is the force the path to the dark side?. Curr Opin Cell Biol 2019; 56: 71-79
153 Greten TF, Schwabe R, Bardeesy N. et al. Immunology and immunotherapy of cholangiocarcinoma. Nat Rev Gastroenterol Hepatol 2023; 20 (06) 349-365
154 Havel JJ, Chowell D, Chan TA. The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. Nat Rev Cancer 2019; 19 (03) 133-150
155 Høgdall D, Lewinska M, Andersen JB. Desmoplastic tumor microenvironment and immunotherapy in cholangiocarcinoma. Trends Cancer 2018; 4 (03) 239-255
156 Hasita H, Komohara Y, Okabe H. et al. Significance of alternatively activated macrophages in patients with intrahepatic cholangiocarcinoma. Cancer Sci 2010; 101 (08) 1913-1919
157 Konishi D, Umeda Y, Yoshida K. et al. Regulatory T cells induce a suppressive immune milieu and promote lymph node metastasis in intrahepatic cholangiocarcinoma. Br J Cancer 2022; 127 (04) 757-765
158 Ma C, Zhang Q, Greten TF. MDSCs in liver cancer: a critical tumor-promoting player and a potential therapeutic target. Cell Immunol 2021; 361: 104295
159 Zimmer CL, Filipovic I, Cornillet M. et al. Mucosal-associated invariant T-cell tumor infiltration predicts long-term survival in cholangiocarcinoma. Hepatology 2022; 75 (05) 1154-1168
160 Kitano Y, Okabe H, Yamashita YI. et al. Tumour-infiltrating inflammatory and immune cells in patients with extrahepatic cholangiocarcinoma. Br J Cancer 2018; 118 (02) 171-180
161 Gao Y, Li J, Cheng W. et al. Cross-tissue human fibroblast atlas reveals myofibroblast subtypes with distinct roles in immune modulation. Cancer Cell 2024; 42 (10) 1764-1783.e10
162 Loeuillard E, Yang J, Buckarma E. et al. Targeting tumor-associated macrophages and granulocytic myeloid-derived suppressor cells augments PD-1 blockade in cholangiocarcinoma. J Clin Invest 2020; 130 (10) 5380-5396
163 Cadamuro M, Brivio S, Mertens J. et al. Platelet-derived growth factor-D enables liver myofibroblasts to promote tumor lymphangiogenesis in cholangiocarcinoma. J Hepatol 2019; 70 (04) 700-709
164 Wynn TA, Ramalingam TR. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat Med 2012; 18 (07) 1028-1040
165 Tacke F, Puengel T, Loomba R, Friedman SL. An integrated view of anti-inflammatory and antifibrotic targets for the treatment of NASH. J Hepatol 2023; 79 (02) 552-566
166 Henderson NC, Rieder F, Wynn TA. Fibrosis: from mechanisms to medicines. Nature 2020; 587 (7835) 555-566
167 Taylor CA, Glover M, Maher J. CAR-T cell technologies that interact with the tumour microenvironment in solid tumours. Expert Rev Clin Immunol 2024; 20 (08) 849-871
168 Sakemura R, Hefazi M, Siegler EL. et al. Targeting cancer-associated fibroblasts in the bone marrow prevents resistance to CART-cell therapy in multiple myeloma. Blood 2022; 139 (26) 3708-3721
169 Liu Y, Sun Y, Wang P. et al. FAP-targeted CAR-T suppresses MDSCs recruitment to improve the antitumor efficacy of claudin18.2-targeted CAR-T against pancreatic cancer. J Transl Med 2023; 21 (01) 255
170 Das S, Valton J, Duchateau P, Poirot L. Stromal depletion by TALEN-edited universal hypoimmunogenic FAP-CAR T cells enables infiltration and anti-tumor cytotoxicity of tumor antigen-targeted CAR-T immunotherapy. Front Immunol 2023; 14: 1172681
171 Lo A, Wang LS, Scholler J. et al. Tumor-promoting desmoplasia is disrupted by depleting FAP-expressing stromal cells. Cancer Res 2015; 75 (14) 2800-2810
172 Schuberth PC, Hagedorn C, Jensen SM. et al. Treatment of malignant pleural mesothelioma by fibroblast activation protein-specific re-directed T cells. J Transl Med 2013; 11: 187
173 Wilson WH, O'Connor OA, Czuczman MS. et al. Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity. Lancet Oncol 2010; 11 (12) 1149-1159
174 Hiltbrunner S, Britschgi C, Schuberth P. et al. Local delivery of CAR T cells targeting fibroblast activation protein is safe in patients with pleural mesothelioma: first report of FAPME, a phase I clinical trial. Ann Oncol 2021; 32 (01) 120-121
175 Petrausch U, Schuberth PC, Hagedorn C. et al. Re-directed T cells for the treatment of fibroblast activation protein (FAP)-positive malignant pleural mesothelioma (FAPME-1). BMC Cancer 2012; 12: 615
176 Melero I, Tanos T, Bustamante M. et al. A first-in-human study of the fibroblast activation protein-targeted, 4-1BB agonist RO7122290 in patients with advanced solid tumors. Sci Transl Med 2023; 15 (695) eabp9229
177 Zhai X, Mao L, Wu M, Liu J, Yu S. Challenges of anti-mesothelin CAR-T-cell therapy. Cancers (Basel) 2023; 15 (05) 15
178 Huang H, Wang Z, Zhang Y. et al. Mesothelial cell-derived antigen-presenting cancer-associated fibroblasts induce expansion of regulatory T cells in pancreatic cancer. Cancer Cell 2022; 40 (06) 656-673.e7
179 Amit U, Uslu U, Verginadis II. et al. Proton radiation boosts the efficacy of mesothelin-targeting chimeric antigen receptor T cell therapy in pancreatic cancer. Proc Natl Acad Sci U S A 2024; 121 (31) e2403002121
180 Schoutrop E, El-Serafi I, Poiret T. et al. Mesothelin-specific CAR T cells target ovarian cancer. Cancer Res 2021; 81 (11) 3022-3035
181 Li F, Zhao S, Wei C. et al. Development of Nectin4/FAP-targeted CAR-T cells secreting IL-7, CCL19, and IL-12 for malignant solid tumors. Front Immunol 2022; 13: 958082
182 Wehrli M, Guinn S, Birocchi F. et al. Mesothelin CAR T cells secreting anti-FAP/anti-CD3 molecules efficiently target pancreatic adenocarcinoma and its stroma. Clin Cancer Res 2024; 30 (09) 1859-1877
183 Ash SL, Orha R, Mole H. et al. Targeting the activated microenvironment with endosialin (CD248)-directed CAR-T cells ablates perivascular cells to impair tumor growth and metastasis. J Immunother Cancer 2024; 12 (02) 12
184 Van den Eynde A, Gehrcken L, Verhezen T. et al. IL-15-secreting CAR natural killer cells directed toward the pan-cancer target CD70 eliminate both cancer cells and cancer-associated fibroblasts. J Hematol Oncol 2024; 17 (01) 8
185 Pal SK, Tran B, Haanen JBAG. et al. CD70-targeted allogeneic CAR T-cell therapy for advanced clear cell renal cell carcinoma. Cancer Discov 2024; 14 (07) 1176-1189
186 Belle JI, Sen D, Baer JM. et al. Senescence defines a distinct subset of myofibroblasts that orchestrates immunosuppression in pancreatic cancer. Cancer Discov 2024; 14 (07) 1324-1355
187 Ye J, Baer JM, Faget DV. et al. Senescent CAFs mediate immunosuppression and drive breast cancer progression. Cancer Discov 2024; 14 (07) 1302-1323
188 Nicolás-Boluda A, Vaquero J, Laurent G. et al. Photothermal depletion of cancer-associated fibroblasts normalizes tumor stiffness in desmoplastic cholangiocarcinoma. ACS Nano 2020; 14 (05) 5738-5753
189 Nicolas-Boluda A, Vaquero J, Vimeux L. et al. Tumor stiffening reversion through collagen crosslinking inhibition improves T cell migration and anti-PD-1 treatment. eLife 2021; 10: 10
190 Lewinska M, Zhuravleva E, Satriano L. et al. Fibroblast-derived lysyl oxidase increases oxidative phosphorylation and stemness in cholangiocarcinoma. Gastroenterology 2024; 166 (05) 886-901.e7
191 Harrison SA, Abdelmalek MF, Caldwell S. et al; GS-US-321-0105 and GS-US-321-0106 Investigators. Simtuzumab is ineffective for patients with bridging fibrosis or compensated cirrhosis caused by nonalcoholic steatohepatitis. Gastroenterology 2018; 155 (04) 1140-1153
192 Arteel GE, Naba A. The liver matrisome—looking beyond collagens. JHEP Rep Innov Hepatol 2020; 2 (04) 100115
193 Goyal L, Zheng H, Yurgelun MB. et al. A phase 2 and biomarker study of cabozantinib in patients with advanced cholangiocarcinoma. Cancer 2017; 123 (11) 1979-1988
194 Kakkar T, Ma M, Zhuang Y, Patton A, Hu Z, Mounho B. Pharmacokinetics and safety of a fully human hepatocyte growth factor antibody, AMG 102, in cynomolgus monkeys. Pharm Res 2007; 24 (10) 1910-1918
195 Kostallari E, Wei B, Sicard D. et al. Stiffness is associated with hepatic stellate cell heterogeneity during liver fibrosis. Am J Physiol Gastrointest Liver Physiol 2022; 322 (02) G234-G246
196 Krenkel O, Hundertmark J, Ritz TP, Weiskirchen R, Tacke F. Single cell RNA sequencing identifies subsets of hepatic stellate cells and myofibroblasts in liver fibrosis. Cells 2019; 8 (05) 8
197 Jeong JM, Choi SE, Shim YR. et al. CX 3 CR1 + macrophages interact with HSCs to promote HCC through CD8 + T-cell suppression. Hepatology 2024; . Epub ahead of print
198 Höchst B, Schildberg FA, Sauerborn P. et al. Activated human hepatic stellate cells induce myeloid derived suppressor cells from peripheral blood monocytes in a CD44-dependent fashion. J Hepatol 2013; 59 (03) 528-535
199 Xu Y, Zhao W, Xu J. et al. Activated hepatic stellate cells promote liver cancer by induction of myeloid-derived suppressor cells through cyclooxygenase-2. Oncotarget 2016; 7 (08) 8866-8878
200 Seki E, Schwabe RF. Hepatic inflammation and fibrosis: functional links and key pathways. Hepatology 2015; 61 (03) 1066-1079
201 Flavell RA, Sanjabi S, Wrzesinski SH, Licona-Limón P. The polarization of immune cells in the tumour environment by TGFbeta. Nat Rev Immunol 2010; 10 (08) 554-567
202 Cheng Y, Li H, Deng Y. et al. Cancer-associated fibroblasts induce PDL1+ neutrophils through the IL6-STAT3 pathway that foster immune suppression in hepatocellular carcinoma. Cell Death Dis 2018; 9 (04) 422
203 Oh DY, Ikeda M, Lee CK. et al. Bintrafusp alfa and chemotherapy as first-line treatment in biliary tract cancer: a randomized phase 2/3 trial. Hepatology 2025; 81 (03) 823-836
204 Xu J, Lin H, Wu G, Zhu M, Li M. IL-6/STAT3 is a promising therapeutic target for hepatocellular carcinoma. Front Oncol 2021; 11: 760971