Insights in the Immune Molecular Mechanisms of the Trilogy of Liver Cancer

Abstract

Liver cancer ranks as the sixth most common cancer globally, with hepatocellular carcinoma (HCC) being its predominant form, accounting for 90% of cases. HCC is closely linked to chronic inflammation and fibrosis driven by factors such as hepatitis B and C, alcoholic liver disease, and metabolic dysfunction-associated steatotic liver disease (MASLD). In the liver, persistent regenerative responses trigger activation of hepatic stellate cells (HSCs), collagen deposition, and fibrosis, which collectively pave the way for carcinogenesis. For patients diagnosed in the early stages of liver cancer, curative options such as surgical resection or liver transplantation may be viable. However, the majority of cases are diagnosed at advanced stages, rendering surgical intervention unsuitable. Systemic treatments for advanced liver cancer often show limited efficacy, highlighting the importance of understanding liver cancer’s development processes to enhance early diagnosis and therapeutic strategies. This review delves into the molecular mechanisms underpinning the progression of liver cancer, tracing the pathological continuum from hepatitis to cirrhosis and ultimately to liver cancer. It explores the immune responses activated during this transition, particularly focusing on inflammatory responses and their central roles. Furthermore, it highlights the significance of inflammatory cytokines and HSCs in liver fibrosis, which creates a microenvironment conducive to cancer development. The review also examines immune regulation and cell signaling in the tumor microenvironment, offering insights into the transformation from hepatitis to liver cancer and paving the way for improved treatment strategies.

Keywords

Hepatitis / Liver fibrosis / Liver cancer / Inflammatory microenvironment / Immune regulation / Cell signal transduction

References

[1] Aberle H, Bauer A, Stappert J, Kispert A, Kemler R. β-catenin is a target for the ubiquitin-proteasome pathway. EMBO J. 1997, 16, 3797-3804. DOI:10.1093/emboj/16.13.3797

[2] Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA A Cancer J. Clin. 2021, 71, 209-249. DOI:10.3322/caac.21660

[3] Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin DM, Piñeros M, et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int. J. Cancer 2019, 144, 1941-1953. DOI:10.1002/ijc.31937

[4] Wang F, Fan J, Zhang Z, Gao B, Wang H. The global burden of liver disease: The major impact of China. Hepatology 2014, 60, 2099-2108. DOI:10.1002/hep.27406

[5] Xiong L, Wu F, Wu Q, Xu L, Cheung OK, Kang W, et al. Aberrant enhancer hypomethylation contributes to hepatic carcinogenesis through global transcriptional reprogramming. Nat. Commun. 2019, 10, 335. DOI:10.1038/s41467-018-08245-z

[6] Athavale D, Song Z, Desert R, Han H, Das S, Ge X, et al. Ablation of high-mobility group box-1 in the liver reduces hepatocellular carcinoma but causes hyperbilirubinemia in Hippo signaling-deficient mice. Hepatol. Commun. 2022, 6, 2155-2169. DOI:10.1002/hep4.1943

[7] Sové RJ, Verma BK, Wang H, Ho WJ, Yarchoan M, Popel AS. Virtual clinical trials of anti-PD-1 and anti-CTLA-4 immunotherapy in advanced hepatocellular carcinoma using a quantitative systems pharmacology model. J. Immunother. Cancer 2022, 10, e005414. DOI:10.1136/jitc-2022-005414

[8] Sung YC, Liu YC, Chao PH, Chang CC, Jin PR, Lin TT, et al. Combined delivery of sorafenib and a MEK inhibitor using CXCR4-targeted nanoparticles reduces hepatic fibrosis and prevents tumor development. Theranostics 2018, 8, 894-905. DOI:10.7150/thno.21168

[9] Tse APW, Sze KMF, Shea QTK, Chiu EYT, Tsang FHC, Chiu DKC, et al. Hepatitis transactivator protein X promotes extracellular matrix modification through HIF/LOX pathway in liver cancer. Oncogenesis 2018, 7, 44. DOI:10.1038/s41389-018-0052-8

[10] Cui Y, Zhang P, Liang X, Xu J, Liu X, Wu Y, et al. Association of KDR mutation with better clinical outcomes in pancancer for immune checkpoint inhibitors. Am. J. Cancer Res. 2022, 12, 1766-1783. Available online: https://pmc.ncbi.nlm.nih.gov/articles/PMC9077071/. (accessed on 1 June 2026).

[11] Roessler D, Öcal O, Philipp AB, Markwardt D, Munker S, Mayerle J, et al. Ipilimumab and nivolumab in advanced hepatocellular carcinoma after failure of prior immune checkpoint inhibitor-based combination therapies: A multicenter retrospective study. J. Cancer Res. Clin. Oncol. 2023, 149, 3065-3073. DOI:10.1007/s00432-022-04206-8

[12] Rizzo AM, Colombo I, Montorfano G, Zava S, Corsetto PA. Exogenous Fatty Acids Modulate ER Lipid Composition and Metabolism in Breast Cancer Cells. Cells 2021, 10, 175. DOI:10.3390/cells10010175

[13] Yin S, Wang H, Bertola A, Feng D, Xu MJ, Wang Y, et al. Activation of invariant natural killer T cells impedes liver regeneration by way of both IFN-γ- and IL-4-dependent mechanisms. Hepatology 2014, 60, 1356-1366. DOI:10.1002/hep.27128

[14] Lee SH. Hyperoxia accelerates progression of hepatic fibrosis by up-regulation of transforming growth factor- β expression. World J. Gastroenterol. 2014, 20, 3011. DOI:10.3748/wjg.v20.i11.3011

[15] Xu K, Shi M, Zhang W, Shi Y, Dong Q, Shen X, et al. Preoperative Fibrosis-4 (FIB-4) Evaluation May Be Helpful to Evaluate Prognosis of Gastric Cancer Patients Undergoing Operation: A Retrospective Study. Front. Oncol. 2021, 11, 655343. DOI:10.3389/fonc.2021.655343

[16] Lingala S, Lau DT, Koh C, Auh S, Ghany MG, Hoofnagle JH. Long-term lamivudine therapy in chronic hepatitis B. Aliment. Pharmacol. Ther. 2016, 44, 380-389. DOI:10.1111/apt.13707

[17] Raimond VC, Feldman WB, Rome BN, Kesselheim AS. Why France Spends Less Than the United States on Drugs: A Comparative Study of Drug Pricing and Pricing Regulation. Milbank Q. 2021, 99, 240-272. DOI:10.1111/1468-0009.12507

[18] Zhang C, Zhang M, Qiu W, Ma H, Zhang X, Zhu Z, et al. Safety and efficacy of tocilizumab versus azathioprine in highly relapsing neuromyelitis optica spectrum disorder (TANGO): An open-label, multicentre, randomised, phase 2 trial. Lancet Neurol. 2020, 19, 391-401. DOI:10.1016/S1474-4422(20)30070-3

[19] Ruan B, Duan JL, Xu H, Tao KS, Han H, Dou GR, et al. Capillarized Liver Sinusoidal Endothelial Cells Undergo Partial Endothelial-Mesenchymal Transition to Actively Deposit Sinusoidal ECM in Liver Fibrosis. Front. Cell Dev. Biol. 2021, 9, 671081. DOI:10.3389/fcell.2021.671081

[20] McDaniel K, Meng F, Wu N, Sato K, Venter J, Bernuzzi F, et al. Forkhead box A2 regulates biliary heterogeneity and senescence during cholestatic liver injury in mice‡. Hepatology 2017, 65, 544-559. DOI:10.1002/hep.28831

[21] Bansal MB, Chamroonkul N. Antifibrotics in liver disease: Are we getting closer to clinical use? Hepatol. Int. 2019, 13, 25-39. DOI:10.1007/s12072-018-9897-3

[22] Li W, Zhou C, Fu Y, Chen T, Liu X, Zhang Z, et al. Targeted delivery of hyaluronic acid nanomicelles to hepatic stellate cells in hepatic fibrosis rats. Acta Pharm. Sin. B 2020, 10, 693-710. DOI:10.1016/j.apsb.2019.07.003

[23] Li Z, Zhou Y, Zhang L, Jia K, Wang S, Wang M, et al. microRNA-199a-3p inhibits hepatic apoptosis and hepatocarcinogenesis by targeting PDCD4. Oncogenesis 2020, 9, 95. DOI:10.1038/s41389-020-00282-y

[24] Hsiao HB, Chou AH, Lin SI, Chen IH, Lien SP, Liu CC, et al. Toll-Like Receptor 9-Mediated Protection of Enterovirus 71 Infection in Mice Is Due to the Release of Danger-Associated Molecular Patterns. J. Virol. 2014, 88, 11658-11670. DOI:10.1128/JVI.00867-14

[25] Mohammed S, Thadathil N, Selvarani R, Nicklas EH, Wang D, Miller BF, et al. Necroptosis contributes to chronic inflammation and fibrosis in aging liver. Aging Cell 2021, 20, e13512. DOI:10.1111/acel.13512

[26] Wu Y, Wu M, Ming S, Zhan X, Hu S, Li X, et al. TREM-2 promotes Th1 responses by interacting with the CD3C-ZAP70 complex following Mycobacterium tuberculosis infection. J. Clin. Investig. 2021, 131, e137407. DOI:10.1172/JCI137407

[27] Ji P, Zhou Y, Yang Y, Wu J, Zhou H, Quan W, et al. Myeloid cell-derived LL-37 promotes lung cancer growth by activating Wnt/β-catenin signaling. Theranostics 2019, 9, 2209-2223. DOI:10.7150/thno.30726

[28] Mchedlidze T, Waldner M, Zopf S, Walker J, Rankin AL, Schuchmann M, et al. Interleukin-33-Dependent Innate Lymphoid Cells Mediate Hepatic Fibrosis. Immunity 2013, 39, 357-371. DOI:10.1016/j.immuni.2013.07.018

[29] Li B, Dorrell C, Canaday PS, Pelz C, Haft A, Finegold M, et al. Adult Mouse Liver Contains Two Distinct Populations of Cholangiocytes. Stem Cell Rep. 2017, 9, 478-489. DOI:10.1016/j.stemcr.2017.06.003

[30] Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat. Rev. Immunol. 2005, 5, 953-964. DOI:10.1038/nri1733

[31] Dai E, Han L, Liu J, Xie Y, Kroemer G, Klionsky DJ, et al. Autophagy-dependent ferroptosis drives tumor-associated macrophage polarization via release and uptake of oncogenic KRAS protein. Autophagy 2020, 16, 2069-2083. DOI:10.1080/15548627.2020.1714209

[32] García-Ruiz I, Blanes Ruiz N, Rada P, Pardo V, Ruiz L, Blas-García A, et al. Protein tyrosine phosphatase 1b deficiency protects against hepatic fibrosis by modulating nadph oxidases. Redox Biol. 2019, 26, 101263. DOI:10.1016/j.redox.2019.101263

[33] Yotsumoto K, Sanui T, Tanaka U, Yamato H, Alshargabi R, Shinjo T, et al. Amelogenin Downregulates Interferon Gamma-Induced Major Histocompatibility Complex Class II Expression Through Suppression of Euchromatin Formation in the Class II Transactivator Promoter IV Region in Macrophages. Front. Immunol. 2020, 11, 709. DOI:10.3389/fimmu.2020.00709

[34] Benner B, Scarberry L, Suarez-Kelly LP, Duggan MC, Campbell AR, Smith E, et al. Generation of monocyte-derived tumor-associated macrophages using tumor-conditioned media provides a novel method to study tumor-associated macrophages in vitro. J. Immunother. Cancer 2019, 7, 140. DOI:10.1186/s40425-019-0622-0

[35] Capuano C, Battella S, Pighi C, Franchitti L, Turriziani O, Morrone S, et al. Tumor-Targeting Anti-CD 20 Antibodies Mediate In Vitro Expansion of Memory Natural Killer Cells: Impact of CD16 Affinity Ligation Conditions and In Vivo Priming. Front. Immunol. 2018, 9, 1031. DOI:10.3389/fimmu.2018.01031

[36] Kerstetter-Fogle A, Shukla S, Wang C, Beiss V, Harris PLR, Sloan AE, et al. Plant Virus-Like Particle In Situ Vaccine for Intracranial Glioma Immunotherapy. Cancers 2019, 11, 515. DOI:10.3390/cancers11040515

[37] Lacatusu I, Iordache TA, Mihaila M, Mihaiescu DE, Pop AL, Badea N. Multifaced Role of Dual Herbal Principles Loaded-Lipid Nanocarriers in Providing High Therapeutic Efficacity. Pharmaceutics 2021, 13, 1511. DOI:10.3390/pharmaceutics13091511

[38] Lee WW, Kang SW, Choi J, Lee SH, Shah K, Eynon EE, et al. Regulating human Th17 cells via differential expression of IL-1 receptor. Blood 2010, 115, 530-540. DOI:10.1182/blood-2009-08-236521

[39] Tan Z, Qian X, Jiang R, Liu Q, Wang Y, Chen C, et al. IL-17A Plays a Critical Role in the Pathogenesis of Liver Fibrosis through Hepatic Stellate Cell Activation. J. Immunol. 2013, 191, 1835-1844. DOI:10.4049/jimmunol.1203013

[40] Meng F, Wang K, Aoyama T, Grivennikov SI, Paik Y, Scholten D, et al. Interleukin-17 Signaling in Inflammatory, Kupffer Cells, and Hepatic Stellate Cells Exacerbates Liver Fibrosis in Mice. Gastroenterology 2012, 143, 765-776.e3. DOI:10.1053/j.gastro.2012.05.049

[41] Prieto J. Inflammation, HCC and sex: IL-6 in the centre of the triangle. J. Hepatol. 2008, 48, 380-381. DOI:10.1016/j.jhep.2007.11.007

[42] Lan T, Chang L, Wu L, Yuan YF. IL-6 Plays a Crucial Role in HBV Infection. J. Clin. Transl. Hepatol. 2015, 3, 271-276. DOI:10.14218/JCTH.2015.00024

[43] Hu Z, Luo D, Wang D, Ma L, Zhao Y, Li L. IL-17 Activates the IL-6/STAT3 Signal Pathway in the Proliferation of Hepatitis B Virus-Related Hepatocellular Carcinoma. Cell Physiol. Biochem. 2017, 43, 2379-2390. DOI:10.1159/000484390

[44] Quetier I, Brezillon N, Revaud J, Ahodantin J, DaSilva L, Soussan P, et al. C-terminal-truncated hepatitis B virus X protein enhances the development of diethylnitrosamine-induced hepatocellular carcinogenesis. J. Gen. Virol. 2015, 96, 614-625. DOI:10.1099/vir.0.070680-0

[45] Jiang R, Tan Z, Deng L, Chen Y, Xia Y, Gao Y, et al. Interleukin-22 promotes human hepatocellular carcinoma by activation of STAT3. Hepatology 2011, 54, 900-909. DOI:10.1002/hep.24486

[46] Dong G, Huang X, Jiang S, Ni L, Chen S. Simvastatin Mitigates Apoptosis and Transforming Growth Factor-Beta Upregulation in Stretch-Induced Endothelial Cells. Oxidative Med. Cell. Longev. 2019, 2019, 6026051. DOI:10.1155/2019/6026051

[47] Shi M, Zhu J, Wang R, Chen X, Mi L, Walz T, et al. Latent TGF- β structure and activation. Nature 2011, 474, 343-349. DOI:10.1038/nature10152

[48] Robertson IB, Rifkin DB. Regulation of the Bioavailability of TGF- β and TGF- β-Related Proteins. Cold Spring Harb. Perspect. Biol. 2016, 8, a021907. DOI:10.1101/cshperspect.a021907

[49] Nishimura SL. Integrin-Mediated Transforming Growth Factor- β Activation, a Potential Therapeutic Target in Fibrogenic Disorders. Am. J. Pathol. 2009, 175, 1362-1370. DOI:10.2353/ajpath.2009.090393

[50] Fan W, Liu T, Chen W, Hammad S, Longerich T, Hausser I, et al. ECM1 Prevents Activation of Transforming Growth Factor β Hepatic Stellate Cells, and Fibrogenesis in Mice. Gastroenterology 2019, 157, 1352-1367.e13. DOI:10.1053/j.gastro.2019.07.036

[51] Khan Z, Marshall JF. The role of integrins in TGFβ activation in the tumour stroma. Cell Tissue Res. 2016, 365, 657-673. DOI:10.1007/s00441-016-2474-y

[52] Fan C, Wang Q, van der Zon G, Ren J, Agaser C, Slieker RC, et al. OVOL1 inhibits breast cancer cell invasion by enhancing the degradation of TGF- β type I receptor. Signal Transduct. Target. Ther. 2022, 7, 126. DOI:10.1038/s41392-022-00944-w

[53] Dewidar B, Meyer C, Dooley S, Meindl-Beinker AN. TGF- β in Hepatic Stellate Cell Activation and Liver Fibrogenesis- Updated 2019. Cells 2019, 8, 1419. DOI:10.3390/cells8111419

[54] Morén A, Bellomo C, Tsubakihara Y, Kardassis D, Mikulits W, Heldin CH, et al. LXRα limits TGFβ-dependent hepatocellular carcinoma associated fibroblast differentiation. Oncogenesis 2019, 8, 36. DOI:10.1038/s41389-019-0140-4

[55] Zhou MY, Cheng ML, Huang T, Hu RH, Zou GL, Li H, et al. Transforming growth factor beta-1 upregulates glucose transporter 1 and glycolysis through canonical and noncanonical pathways in hepatic stellate cells. World J. Gastroenterol. 2021, 27, 6908-6926. DOI:10.3748/wjg.v27.i40.6908

[56] Ma L, Zeng Y, Wei J, Yang D, Ding G, Liu J, et al. Knockdown of LOXL. inhibits TGF- β1-induced proliferation and fibrogenesis of hepatic stellate cells by inhibition of Smad2/3 phosphorylation. Biomed. Pharmacother. 2018, 107, 1728-1735. DOI:10.1016/j.biopha.2018.08.156

[57] Henderson NC, Arnold TD, Katamura Y, Giacomini MM, Rodriguez JD, McCarty JH, et al. Targeting of av integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nat. Med. 2013, 19, 1617-1624. DOI:10.1038/nm.3282

[58] Park HJ, Gusarova G, Wang Z, Carr JR, Li J, Kim K, et al. Deregulation of FoxM1b leads to tumour metastasis. EMBO Mol. Med. 2011, 3, 21-34. DOI:10.1002/emmm.201000107

[59] Li XM, Peng JH, Sun ZL, Tian HJ, Duan XH, Liu L, et al. Chinese medicine CGA formula ameliorates DMN-induced liver fibrosis in rats via inhibiting MMP2/9, TIMP1/2 and the TGF- β /Smad signaling pathways. Acta Pharmacol. Sin. 2016, 37, 783-793. DOI:10.1038/aps.2016.35

[60] Zhang Z, Xu J, Zhang X, Wang J, Xie H, Sun Y, et al. Protective Effect of SeMet on Liver Injury Induced by Ochratoxin A in Rabbits. Toxins 2022, 14, 628. DOI:10.3390/toxins14090628

[61] Xi Y, Li Y, Xu P, Li S, Liu Z, Tung HC, et al. The anti-fibrotic drug pirfenidone inhibits liver fibrosis by targeting the small oxidoreductase glutaredoxin-1. Sci. Adv. 2021, 7, eabg9241. DOI:10.1126/sciadv.abg9241

[62] Yin C, Evason KJ, Asahina K, Stainier DYR. Hepatic stellate cells in liver development, regeneration, and cancer. J. Clin. Investig. 2013, 123, 1902-1910. DOI:10.1172/JCI66369

[63] Khaja F, Jayawardena D, Kuzmis A, Önyüksel H. Targeted Sterically Stabilized Phospholipid siRNA Nanomedicine for Hepatic and Renal Fibrosis. Nanomaterials 2016, 6, 8. DOI:10.3390/nano6010008

[64] Kamada Y, Takahashi H, Ogawa Y, Hyogo H, Nakamura K, Yada T, et al. Characterization of Nutrient Intake in Biopsy-Confirmed NAFLD Patients. Nutrients 2022, 14, 3453. DOI:10.3390/nu14173453

[65] Park JS, Oh Y, Park YJ, Park O, Yang H, Slania S, et al. Targeting of dermal myofibroblasts through death receptor 5 arrests fibrosis in mouse models of scleroderma. Nat. Commun. 2019, 10, 1128. DOI:10.1038/s41467-019-09101-4

[66] Sasaki R, Devhare PB, Steele R, Ray R, Ray RB. Hepatitis C virus-induced CCL 5 secretion from macrophages activates hepatic stellate cells. Hepatology 2017, 66, 746-757. DOI:10.1002/hep.29170

[67] Kaartinen V, Voncken JW, Shuler C, Warburton D, Bu D, Heisterkamp N, et al. Abnormal lung development and cleft palate in mice lacking TGF- β3 indicates defects of epithelial-mesenchymal interaction. Nat. Genet. 1995, 11, 415-421. DOI:10.1038/ng1295-415

[68] Sanford LP, Ormsby I, Groot ACGD, Sariola H, Friedman R, Boivin GP, et al. TGF β2 knockout mice have multiple developmental defects that are non-overlapping with other TGF β knockout phenotypes. Development 1997, 124, 2659-2670. DOI:10.1242/dev.124.13.2659

[69] Fang L, Li Y, Wang S, Li Y, Chang HM, Yi Y, et al. TGF- β1 induces VEGF expression in human granulosa-lutein cells: a potential mechanism for the pathogenesis of ovarian hyperstimulation syndrome. Exp. Mol. Med. 2020, 52, 450-460. DOI:10.1038/s12276-020-0396-y

[70] Ohta M, Chosa N, Kyakumoto S, Yokota S, Okubo N, Nemoto A, et al. IL-1 β and TNF- α suppress TGF- β-promoted NGF expression in periodontal ligament-derived fibroblasts through inactivation of TGF- β-induced Smad2/3- and p38 MAPK-mediated signals. Int. J. Mol. Med. 2018, 42, 1484-1494. DOI:10.3892/ijmm.2018.3714

[71] Meng XM, Nikolic-Paterson DJ, Lan HY. TGF-β: The master regulator fibrosis. Nat. Rev. Nephrol. 2016, 12, 325-338. DOI:10.1038/nrneph.2016.48

[72] Kawelke N, Vasel M, Sens C, von Au A, Dooley S, Nakchbandi IA. Fibronectin Protects from Excessive Liver Fibrosis by Modulating the Availability of and Responsiveness of Stellate Cells to Active TGF- β. PLoS ONE 2011, 6, e28181. DOI:10.1371/journal.pone.0028181

[73] Gurney A, Axelrod F, Bond CJ, Cain J, Chartier C, Donigan L, et al. Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors. Proc. Natl. Acad. Sci. USA 2012, 109, 11717-11722. DOI:10.1073/pnas.1120068109

[74] Olaso E, Ikeda K, Eng FJ, Xu L, Wang LH, Lin HC, et al. DDR2 receptor promotes MMP-2-mediated proliferation and invasion by hepatic stellate cells. J. Clin. Investig. 2001, 108, 1369-1378. DOI:10.1172/JCI200112373

[75] Ojiaku CA, Chung E, Parikh V, Williams JK, Schwab A, Fuentes AL, et al. Transforming Growth Factor- β1 Decreases β2-Agonist-induced Relaxation in Human Airway Smooth Muscle. Am. J. Respir. Cell Mol. Biol. 2019, 61, 209-218. DOI:10.1165/rcmb.2018-0301OC

[76] Altrock E, Sens C, Wuerfel C, Vasel M, Kawelke N, Dooley S, et al. Inhibition of fibronectin deposition improves experimental liver fibrosis. J. Hepatol. 2015, 62, 625-633. DOI:10.1016/j.jhep.2014.06.010

[77] Kisseleva T, Brenner DA. Role of hepatic stellate cells in fibrogenesis and the reversal of fibrosis. J. Gastro Hepatol. 2007, 22, S73-S78. DOI:10.1111/j.1440-1746.2006.04658.x

[78] Troeger JS, Mederacke I, Gwak G, Dapito DH, Mu X, Hsu CC, et al. Deactivation of Hepatic Stellate Cells During Liver Fibrosis Resolution in Mice. Gastroenterology 2012, 143, 1073-1083.e22. DOI:10.1053/j.gastro.2012.06.036

[79] Arroyo N, Villamayor L, Díaz I, Carmona R, Ramos-Rodríguez M, Muñoz-Chápuli R, et al. GATA4 induces liver fibrosis regression by deactivating hepatic stellate cells. JCI Insight 2021, 6, e150059. DOI:10.1172/jci.insight.150059

[80] Pellicoro A, Ramachandran P, Iredale JP, Fallowfield JA. Liver fibrosis and repair: Immune regulation of wound healing in a solid organ. Nat. Rev. Immunol. 2014, 14, 181-194. DOI:10.1038/nri3623

[81] Luedde T, Kaplowitz N, Schwabe RF. Cell Death and Cell Death Responses in Liver Disease: Mechanisms and Clinical Relevance. Gastroenterology 2014, 147, 765-783.e4. DOI:10.1053/j.gastro.2014.07.018

[82] Unitt E, Rushbrook SM, Marshall A, Davies S, Gibbs P, Morris LS, et al. Compromised lymphocytes infiltrate hepatocellular carcinoma. Hepatology 2005, 41, 722-730. DOI:10.1002/hep.20644

[83] Unitt E, Marshall A, Gelson W, Rushbrook SM, Davies S, Vowler SL, et al. Tumour lymphocytic infiltrate and recurrence of hepatocellular carcinoma following liver transplantation. J. Hepatol. 2006, 45, 246-253. DOI:10.1016/j.jhep.2005.12.027

[84] Yuan J, Wang Y, Wang X, Zhang W, Ding R, Yue S, et al. Construction and experimental verification of user-friendly molecular subtypes mediated by immune-associated genes in hepatocellular carcinoma. Front. Oncol. 2022, 12, 924059. DOI:10.3389/fonc.2022.924059

[85] Hu Y, Zeng N, Ge Y, Wang D, Qin X, Zhang W, et al. Identification of the Shared Gene Signatures and Biological Mechanism in Type 2 Diabetes and Pancreatic Cancer. Front. Endocrinol. 2022, 13, 847760. DOI:10.3389/fendo.2022.847760

[86] Wang PW, Lin TY, Yang PM, Yeh CT, Pan TL. Hepatic Stellate Cell Modulates the Immune Microenvironment in the Progression of Hepatocellular Carcinoma. Int. J. Mol. Sci. 2022, 23, 10777. DOI:10.3390/ijms231810777

[87] Mederacke I, Hsu CC, Troeger JS, Huebener P, Mu X, Dapito DH, et al. Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nat. Commun. 2013, 4, 2823. DOI:10.1038/ncomms3823

[88] He S, Luo Y, Ma W, Wang X, Yan C, Hao W, et al. Endothelial POFUT1 controls injury-induced liver fibrosis by repressing fibrinogen synthesis. J. Hepatol. 2024, 81, 135-148. DOI:10.1016/j.jhep.2024.02.032

[89] Sarrazy V, Viaud M, Westerterp M, Ivanov S, Giorgetti-Peraldi S, Guinamard R, et al. Disruption of Glut1 in Hematopoietic Stem Cells Prevents Myelopoiesis and Enhanced Glucose Flux in Atheromatous Plaques of ApoE^(-/-)Mice. Circ. Res. 2016, 118, 1062-1077. DOI:10.1161/CIRCRESAHA.115.307599

[90] Zhao G, Dong R, Teng J, Yang L, Liu T, Wu X, et al. N-Acetyl-L-cysteine Enhances the Effect of Selenium Nanoparticles on Cancer Cytotoxicity by Increasing the Production of Selenium-Induced Reactive Oxygen Species. ACS Omega 2020, 5, 11710-11720. DOI:10.1021/acsomega.0c01034

[91] Hellemans K, Grinko I, Rombouts K, Schuppan D, Geerts A. All-trans and 9-cis retinoic acid alter rat hepatic stellate cell phenotype differentially. Gut 1999, 45, 134-142. DOI:10.1136/gut.45.1.134

[92] Acharya P, Chouhan K, Weiskirchen S, Weiskirchen R. Cellular Mechanisms of Liver Fibrosis. Front. Pharmacol. 2021, 12, 671640. DOI:10.3389/fphar.2021.671640

[93] Han QJ, Mu YL, Zhao HJ, Zhao RR, Guo QJ, Su YH, et al. Fasudil prevents liver fibrosis via activating natural killer cells and suppressing hepatic stellate cells. World J. Gastroenterol. 2021, 27, 3581-3594. DOI:10.3748/wjg.v27.i24.3581

[94] Casson CN, Doerner JL, Copenhaver AM, Ramirez J, Holmgren AM, Boyer MA, et al. Neutrophils and Ly6C ^hi monocytes collaborate in generating an optimal cytokine response that protects against pulmonary Legionella pneumophila infection. PLoS Pathog. 2017, 13, e1006309. DOI:10.1371/journal.ppat.1006309

[95] Knolle PA, Thimme R. Hepatic Immune Regulation and Its Involvement in Viral Hepatitis Infection. Gastroenterology 2014, 146, 1193-1207. DOI:10.1053/j.gastro.2013.12.036

[96] Winau F, Hegasy G, Weiskirchen R, Weber S, Cassan C, Sieling PA, et al. Ito Cells Are Liver-Resident Antigen-Presenting Cells for Activating T Cell Responses. Immunity 2007, 26, 117-129. DOI:10.1016/j.immuni.2006.11.011

[97] Goh CC, Roggerson KM, Lee HC, Golden-Mason L, Rosen HR, Hahn YS. Hepatitis C Virus-Induced Myeloid-Derived Suppressor Cells Suppress NK Cell IFN- γ Production by Altering Cellular Metabolism via Arginase-1. J. Immunol. 2016, 196, 2283-2292. DOI:10.4049/jimmunol.1501881

[98] Hoechst B, Ormandy LA, Ballmaier M, Lehner F, Krüger C, Manns MP, et al. A New Population of Myeloid-Derived Suppressor Cells in Hepatocellular Carcinoma Patients Induces CD4 ^+CD25 ^+Foxp3 ^+T Cells. Gastroenterology 2008, 135, 234-243. DOI:10.1053/j.gastro.2008.03.020

[99] Hoechst B, Voigtlaender T, Ormandy L, Gamrekelashvili J, Zhao F, Wedemeyer H, et al. Myeloid derived suppressor cells inhibit natural killer cells in patients with hepatocellular carcinoma via the NKp 30 receptor ^#. Hepatology 2009, 50, 799-807. DOI:10.1002/hep.23054

[100] Wang YH, Hou HA, Lin CC, Kuo YY, Yao CY, Hsu CL, et al. A CIBERSORTx-based immune cell scoring system could independently predict the prognosis of patients with myelodysplastic syndromes. Blood Adv. 2021, 5, 4535-4548. DOI:10.1182/bloodadvances.2021005141

[101] Hafez MM, Hamed SS, El-Khadragy MF, Hassan ZK, Al Rejaie SS, Sayed-Ahmed MM, et al. Effect of ginseng extract on the TGF- β1 signaling pathway in CC14-induced liver fibrosis in rats. BMC Complement. Altern. Med. 2017, 17, 45. DOI:10.1186/s12906-016-1507-0

[102] Höchst B, Schildberg FA, Sauerborn P, Gäbel YA, Gevensleben H, Goltz D, 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, 528-535. DOI:10.1016/j.jhep.2013.04.033

[103] Tarantino G, Citro V. Liver-spleen axis: Deciphering a crucial crosstalk in non-alcoholic fatty liver disease progression and therapeutic implications. World J. Gastroenterol. 2026, 32, 119467. DOI:10.3748/wjg.119467

[104] Laparra Llopis JM, Brown D, Saiz B. Chenopodium Quinoa and Salvia Hispanica Provide Immunonutritional Agonists to Ameliorate Hepatocarcinoma Severity under a High-Fat Diet. Nutrients 2020, 12, 1946. DOI:10.3390/nu12071946

[105] Ma C, Kesarwala AH, Eggert T, Medina-Echeverz J, Kleiner DE, Jin P, et al. NAFLD causes selective CD 4 ^+T lymphocyte loss and promotes hepatocarcinogenesis. Nature 2016, 531, 253-257. DOI:10.1038/nature16969

[106] Satriano L, Lewinska M, Rodrigues PM, Banales JM, Andersen JB. Metabolic rearrangements in primary liver cancers: Cause and consequences. Nat. Rev. Gastroenterol. Hepatol. 2019, 16, 748-766. DOI:10.1038/s41575-019-0217-8

[107] Atarashi M, Izawa T, Mori M, Inai Y, Kuwamura M, Yamate J. Dietary Iron Overload Abrogates Chemically-Induced Liver Cirrhosis in Rats. Nutrients 2018, 10, 1400. DOI:10.3390/nu10101400

[108] Bu P, Chen KY, Xiang K, Johnson C, Crown SB, Rakhilin N, et al. Aldolase B-Mediated Fructose Metabolism Drives Metabolic Reprogramming of Colon Cancer Liver Metastasis. Cell Metab. 2018, 27, 1249-1262.e4. DOI:10.1016/j.cmet.2018.04.003

[109] Bolatai A, He Y, Wu N. Vascular endothelial growth factor and its receptors regulation in gestational diabetes mellitus and eclampsia. J. Transl. Med. 2022, 20, 400. DOI:10.1186/s12967-022-03603-4

[110] Kessler T, Sahm F, Blaes J, Osswald M, Rübmann P, Milford D, et al. Glioma cell VEGFR-2 confers resistance to chemotherapeutic and antiangiogenic treatments in PTEN-deficient glioblastoma. Oncotarget 2015, 6, 31050-31068. DOI:10.18632/oncotarget.2910

[111] Faes S, Santoro T, Demartines N, Dormond O. Evolving Significance and Future Relevance of Anti-Angiogenic Activity of mTOR Inhibitors in Cancer Therapy. Cancers 2017, 9, 152. DOI:10.3390/cancers9110152

[112] Mercurio AM, Lipscomb EA, Bachelder RE. J. Mammary Gland. Biol. Non-Angiogenic Functions of VEGF in Breast Cancer. Neoplasia 2005, 10, 283-290. DOI:10.1007/s10911-006-9001-9

[113] Feng R, Morine Y, Ikemoto T, Imura S, Iwahashi S, Saito Y, et al. Nrf2 activation drive macrophages polarization and cancer cell epithelial-mesenchymal transition during interaction. Cell Commun. Signal 2018, 16, 54. DOI:10.1186/s12964-018-0262-x

[114] Okikawa S, Morine Y, Saito Y, Yamada S, Tokuda K, Teraoku H, et al. Inhibition of the VEGF signaling pathway attenuates tumor-associated macrophage activity in liver cancer. Oncol. Rep. 2022, 47, 71. DOI:10.3892/or.2022.8282

[115] Cheng AL, Kang YK, Lin DY, Park JW, Kudo M, Qin S, et al. Sunitinib Versus Sorafenib in Advanced Hepatocellular Cancer: Results of a Randomized Phase III Trial. J. Clin. Oncol. 2013, 31, 4067-4075. DOI:10.1200/JCO.2012.45.8372

[116] Llovet JM, Montal R, Villanueva A. Randomized trials and endpoints in advanced HCC: Role of PFS as a surrogate of survival. J. Hepatol. 2019, 70, 1262-1277. DOI:10.1016/j.jhep.2019.01.028

[117] Behrens J, Jerchow BA, Würtele M, Grimm J, Asbrand C, Wirtz R, et al. Functional Interaction of an Axin Homolog, Conductin, with β-Catenin, APC, and GSK3β. Science 1998, 280, 596-599. DOI:10.1126/science.280.5363.596

[118] Kimelman D, Xu W. β-Catenin destruction complex: Insights and questions from a structural perspective. Oncogene 2006, 25, 7482-7491. DOI:10.1038/sj.onc.1210055

[119] Liu C, Li Y, Semenov M, Han C, Baeg GH, Tan Y, et al. Control of β-Catenin Phosphorylation/Degradation by a Dual-Kinase Mechanism. Cell 2002, 108, 837-847. DOI:10.1016/S0092-8674(02)00685-2

[120] Amit S, Hatzubai A, Birman Y, Andersen JS, Ben-Shushan E, Mann M, et al. Axin-mediated CKI phosphorylation of β -catenin at Ser 45: A molecular switch for the Wnt pathway. Genes Dev. 2002, 16, 1066-1076. DOI:10.1101/gad.230302

[121] Nejak-Bowen KN, Thompson MD, Singh S, Bowen WC, Dar MJ, Khillan J, et al. Accelerated Liver Regeneration and Hepatocarcinogenesis in Mice Overexpressing Serine-45 Mutant β-Catenin. Hepatology 2010, 51, 1603-1613. DOI:10.1002/hep.23538

[122] Zhang XF, Tan X, Zeng G, Misse A, Singh S, Kim Y, et al. Conditional β-Catenin Loss in Mice Promotes Chemical Hepatocarcinogenesis: Role of Oxidative Stress and Platelet-Derived Growth Factor Receptor α/ Phosphoinositide 3 -Kinase Signaling. Hepatology 2010, 52, 954-965. DOI:10.1002/hep.23747

[123] Delgado E, Okabe H, Preziosi M, Russell JO, Alvarado TF, Oertel M, et al. Complete response of Ctnnb1-mutated tumours to β-catenin suppression by locked nucleic acid antisense in a mouse hepatocarcinogenesis model. J. Hepatol. 2015, 62, 380-387. DOI:10.1016/j.jhep.2014.10.021

[124] Chaudhary B, Elkord E. Regulatory T Cells in the Tumor Microenvironment and Cancer Progression: Role and Therapeutic Targeting. Vaccines 2016, 4, 28. DOI:10.3390/vaccines4030028

[125] Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A. Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy. Cell 2017, 168, 707-723. DOI:10.1016/j.cell.2017.01.017

[126] Van Loosdregt J, Fleskens V, Tiemessen MM, Mokry M, van Boxtel R, Meerding J, et al. Canonical Wnt Signaling Negatively Modulates Regulatory T Cell Function. Immunity 2013, 39, 298-310. DOI:10.1016/j.immuni.2013.07.019

[127] Dai W, Liu F, Li C, Lu Y, Lu X, Du S, et al. Blockade of Wnt /β-Catenin Pathway Aggravated Silica-Induced Lung Inflammation through Tregs Regulation on Th Immune Responses. Mediat. Inflamm. 2016, 2016, 6235614. DOI:10.1155/2016/6235614

[128] Di Piazza M, Nowell CS, Koch U, Durham AD, Radtke F. Loss of Cutaneous TSLP-Dependent Immune Responses Skews the Balance of Inflammation from Tumor Protective to Tumor Promoting. Cancer Cell 2012, 22, 479-493. DOI:10.1016/j.ccr.2012.08.016

[129] You L, Zhang C, Yarravarapu N, Morlock L, Wang X, Zhang L, et al. Development of a triazole class of highly potent Porcn inhibitors. Bioorganic Med. Chem. Lett. 2016, 26, 5891-5895. DOI:10.1016/j.bmcl.2016.11.012

[130] Liu Y, Xun Z, Ma K, Liang S, Li X, Zhou S, et al. Identification of a tumour immune barrier in the HCC microenvironment that determines the efficacy of immunotherapy. J. Hepatol. 2023, 78, 770-782. DOI:10.1016/j.jhep.2023.01.011