Pathophysiology of liver cirrhosis and risk correlation between immune status and the pathogenesis of hepatocellular carcinoma

Abstract

Chronic liver disease (CLD) and cirrhosis are leading contributors to global morbidity and mortality, with hepatocellular carcinoma (HCC) frequently arising in patients with advanced liver damage. This review explores the interplay between immune dysfunction and the progression of cirrhosis to HCC, emphasizing the pivotal role of immune status in HCC pathogenesis. Chronic inflammation, cirrhosis-associated immune dysfunction syndrome (CAIDS), and immunosenescence create a permissive environment for tumorigenesis by impairing immune surveillance and promoting hepatocyte stress. Key mechanisms include T cell exhaustion, dysregulated cytokine signaling, and gut-liver axis dysfunction, which collectively drive malignant transformation. Emerging immune biomarkers, such as PD-1/PD-L1, LAG-3, TIGIT, and soluble CD14/CD163, offer promise for refining HCC risk stratification and improving early detection. Integrating these biomarkers into existing surveillance protocols could enhance screening efficacy, particularly in high-risk populations such as the elderly and immunocompromised. Current guidelines recommend biannual ultrasound and alpha-fetoprotein testing for cirrhotic patients, but adherence remains suboptimal, and late diagnoses are common. A personalized approach combining clinical risk factors, immune markers, and patient demographics may improve surveillance outcomes. Future research should focus on validating immune biomarkers in large cohorts, exploring novel therapeutic targets like LAG-3 and TIGIT, and developing tools to quantify immune dysfunction for risk stratification. By addressing immune dysregulation as a critical factor in HCC development, this review highlights the potential for improved HCC screening adherence and early detection for better patient outcomes through immune-based strategies.

Keywords

Liver cirrhosis / hepatocellular carcinoma (HCC) / risk stratification / immune dysfunction in liver cirrhosis / chronic inflammation in liver cirrhosis / cirrhosis-associated immune dysfunction syndrome (CAIDS) / tumor microenvironment / surveillance

References

[1] Cheemerla S.Global epidemiology of chronic liver disease.Clin Liver Dis2021;17:365-70 PMCID:PMC8177826

[2] Wu XN,Zhang N.Global burden of liver cirrhosis and other chronic liver diseases caused by specific etiologies from 1990 to 2019.BMC Public Health2024;24:363 PMCID:PMC10837876

[3] Nusrat S,Fazili J.Cirrhosis and its complications: evidence based treatment.World J Gastroenterol2014;20:5442-60 PMCID:PMC4017060

[4] Premkumar M.Overview of complications in cirrhosis.J Clin Exp Hepatol2022;12:1150-74 PMCID:PMC9257866

[5] Yang JD,Gores GJ,Plymoth A.A global view of hepatocellular carcinoma: trends, risk, prevention and management.Nat Rev Gastroenterol Hepatol2019;16:589-604 PMCID:PMC6813818

[6] Tejeda-Maldonado J,Aguirre-Valadez J.Diagnosis and treatment of hepatocellular carcinoma: an update.World J Hepatol2015;7:362-76 PMCID:PMC4381163

[7] Ma Y,Xiao W.A review of MASLD-related hepatocellular carcinoma: progress in pathogenesis, early detection, and therapeutic interventions.Front Med2024;11:1410668 PMCID:PMC11184143

[8] Onyirioha K,G Singal A.Is hepatocellular carcinoma surveillance in high-risk populations effective?.Hepat Oncol2020;7:HEP25 PMCID:PMC7399579

[9] Masuzaki R,Omata M.New serum markers of hepatocellular carcinoma.Semin Oncol2012;39:434-9

[10] Attia AM,Hwang SY.Novel biomarkers for early detection of hepatocellular carcinoma.Diagnostics2024;14:2278 PMCID:PMC11507329

[11] Hasa E,Schnabl B.Liver cirrhosis and immune dysfunction.Int Immunol2022;34:455-66 PMCID:PMC9447994

[12] Singh N,Rajguru JP,Thakkannavar SS.Inflammation and cancer.Ann Afr Med2019;18:121-6 PMCID:PMC6704802

[13] Schuppan D.Liver cirrhosis.Lancet2008;371:838-51 PMCID:PMC2271178

[14] Cheng QN,Wu JF,Ni YR.Interaction of nonparenchymal hepatocytes in the process of hepatic fibrosis (Review).Mol Med Rep2021;23:364 PMCID:PMC7986015

[15] Liu SY,Hsu YC.Alcohol-related liver disease: basic mechanisms and clinical perspectives.Int J Mol Sci2021;22:5170 PMCID:PMC8153142

[16] Lakner AM,Walling TL.Inhibitory effects of microRNA 19b in hepatic stellate cell-mediated fibrogenesis.Hepatology2012;56:300-10 PMCID:PMC3342471

[17] Zhou WC,Qiao L.Pathogenesis of liver cirrhosis.World J Gastroenterol2014;20:7312-24 PMCID:PMC4064077

[18] Albillos A,Van der Merwe S,Jalan R.Cirrhosis-associated immune dysfunction.Nat Rev Gastroenterol Hepatol2022;19:112-34

[19] Kronsten VT.Clinical implications of inflammation in patients with cirrhosis.Am J Gastroenterol2025;120:65-74 PMCID:PMC11676607

[20] Rodríguez-Negrete EV,Sánchez-Reyes K.Liver cirrhosis: the immunocompromised state.J Clin Med2024;13:5582 PMCID:PMC11432654

[21] Tuchendler E,Madej G.Immunodeficiency caused by cirrhosis.Clin Exp Hepatol2018;4:158-64 PMCID:PMC6185932

[22] Zhang J,Zhang J.Is it possible to intervene early cirrhosis by targeting toll-like receptors to rebalance the intestinal microbiome?.Int Immunopharmacol2023;115:109627

[23] Fattovich G,Zagni I.Hepatocellular carcinoma in cirrhosis: incidence and risk factors.Gastroenterology2004;127:S35-50

[24] Refolo MG,Guerra V,D’Alessandro R.Inflammatory mechanisms of HCC development.Cancers2020;12:641 PMCID:PMC7139884

[25] Longo M,Meroni M.Remodeling of mitochondrial plasticity: the key switch from NAFLD/NASH to HCC.Int J Mol Sci2021;22:4173 PMCID:PMC8073183

[26] Galasso L,Maccauro V.Inflammatory response in the pathogenesis and treatment of hepatocellular carcinoma: a double-edged weapon.Int J Mol Sci2024;25:7191 PMCID:PMC11241080

[27] Zhou Y,Xu H.Loss of TP53 cooperates with c-MET overexpression to drive hepatocarcinogenesis.Cell Death Dis2023;14:476 PMCID:PMC10374654

[28] Tornesello ML,Starita N.Reactivation of telomerase reverse transcriptase expression in cancer: the role of TERT promoter mutations.Front Cell Dev Biol2023;11:1286683 PMCID:PMC10684755

[29] Fu S,Boonstra A.DNA methylation markers in the detection of hepatocellular carcinoma.Eur J Cancer2023;191:112960

[30] Kim SK.The evasion mechanisms of cancer immunity and drug intervention in the tumor microenvironment.Front Pharmacol2022;13:868695 PMCID:PMC9171538

[31] Allen CT,Van Waes C.Anti-tumor immunity in head and neck cancer: understanding the evidence, how tumors escape and immunotherapeutic approaches.Cancers2015;7:2397-414 PMCID:PMC4695900

[32] Yang Y,Zhao B.The predictive value of PD-L1 expression in patients with advanced hepatocellular carcinoma treated with PD-1/PD-L1 inhibitors: a systematic review and meta-analysis.Cancer Med2023;12:9282-92 PMCID:PMC10166972

[33] Walker LS.Treg and CTLA-4: two intertwining pathways to immune tolerance.J Autoimmun2013;45:49-57 PMCID:PMC3989116

[34] Darmadi D,Siregar J.Association between serum cytotoxic T lymphocyte antigen (CTLA)-4 level and disease progression in patients with chronic hepatitis B.Med Arch2023;77:142-5 PMCID:PMC10227835

[35] Sauer N,Szlasa W.TIM-3 as a promising target for cancer immunotherapy in a wide range of tumors.Cancer Immunol Immunother2023;72:3405-25 PMCID:PMC10576709

[36] Ganjalikhani Hakemi M, Jafarinia M, Azizi M, Rezaeepoor M, Isayev O, Bazhin AV. The role of TIM-3 in hepatocellular carcinoma: a promising target for immunotherapy?.Front Oncol2020;10:601661 PMCID:PMC7793963

[37] Guo M,Qi F.Expression and clinical significance of LAG-3, FGL1, PD-L1 and CD8⁺T cells in hepatocellular carcinoma using multiplex quantitative analysis.J Transl Med2020;18:306 PMCID:PMC7409704

[38] Guo Y,Xia WL.Relationship between TIGIT expression on T cells and the prognosis of patients with hepatocellular carcinoma.BMC Cancer2024;24:1120 PMCID:PMC11382530

[39] Ma C,Greten TF.MDSCs in liver cancer: a critical tumor-promoting player and a potential therapeutic target.Cell Immunol2021;361:104295 PMCID:PMC7882059

[40] Eleftheriadis T,Antoniadi G,Stefanidis I.Indoleamine 2,3-dioxygenase depletes tryptophan, activates general control non-derepressible 2 kinase and down-regulates key enzymes involved in fatty acid synthesis in primary human CD4+ T cells.Immunology2015;146:292-300 PMCID:PMC4582970

[41] Asghar K,Abubakar M.High indoleamine 2,3-dioxygenase expression along with low bridging integrator-1 expression in hepatocellular carcinoma patients.Asian Pac J Cancer Prev2023;24:1591-600 PMCID:PMC10495885

[42] Nenu I,Topor I.Interleukin-6 in hepatocellular carcinoma: a dualistic point of view.Biomedicines2023;11:2623 PMCID:PMC10603956

[43] Tan W,Li W.TNF-α is a potential therapeutic target to overcome sorafenib resistance in hepatocellular carcinoma.EBioMedicine2019;40:446-56 PMCID:PMC6412090

[44] Jin X,Wang N.High expression of TGF-β1 contributes to hepatocellular carcinoma prognosis via regulating tumor immunity.Front Oncol2022;12:861601 PMCID:PMC9082360

[45] Lee HA,Lee YS.Natural killer cell activity is a risk factor for the recurrence risk after curative treatment of hepatocellular carcinoma.BMC Gastroenterol2021;21:258 PMCID:PMC8199695

[46] Li N,Yang C.Elevated serum soluble CD14 levels in chronic HBV infection are significantly associated with HBV-related hepatocellular carcinoma.Tumour Biol2016;37:6607-17

[47] Kawanaka M,Kawada M.Soluble CD163 is a predictor of fibrosis and hepatocellular carcinoma development in nonalcoholic steatohepatitis.BMC Gastroenterol2023;23:143 PMCID:PMC10173513

[48] Haas OA.Primary immunodeficiency and cancer predisposition revisited: embedding two closely related concepts into an integrative conceptual framework.Front Immunol2018;9:3136 PMCID:PMC6379258

[49] Pai SY,Yarchoan R.How immunodeficiency can lead to malignancy.Hematology Am Soc Hematol Educ Program2021;2021:287-95 PMCID:PMC8791117

[50] Kallingal A,Maciejewska N,Baginski M.Cancer immune escape: the role of antigen presentation machinery.J Cancer Res Clin Oncol2023;149:8131-41 PMCID:PMC10374767

[51] Lian J,Yu W.Immunosenescence: a key player in cancer development.J Hematol Oncol2020;13:151 PMCID:PMC7653700

[52] Fu Z,Yue L.Immunosenescence and cancer: opportunities and challenges.Medicine2023;102:e36045 PMCID:PMC10681516

[53] Li R,Luo W,Luo B.Identification of immunosenescence of unconventional T cells in hepatocellular carcinoma.Comput Biol Chem2024;112:108148

[54] Cogliati B,Wang S,Friedman SL.Friend or foe? The elusive role of hepatic stellate cells in liver cancer.Nat Rev Gastroenterol Hepatol2023;20:647-61 PMCID:PMC10671228

[55] Ramakrishna G,Trehanpati N,Khosla R.From cirrhosis to hepatocellular carcinoma: new molecular insights on inflammation and cellular senescence.Liver Cancer2013;2:367-83 PMCID:PMC3881319

[56] Tarao K,Ikeda T.Real impact of liver cirrhosis on the development of hepatocellular carcinoma in various liver diseases-meta-analytic assessment.Cancer Med2019;8:1054-65 PMCID:PMC6434205