Education, Science, Technology, Innovation and Life
Open Access
Sign In
  1. Home
  2. Journals
  3. MEDS Clinical Medicine
  4. Vol 7, Issue 2, 2026

Hepatitis B-Induced Immunological Remodeling in Hepatocellular Carcinoma

Download as PDF

DOI: 10.23977/medsc.2026.070210 | Downloads: 0 | Views: 76

Author(s)

Jiaxiang Li 1, Haiyang Yan 1

Affiliation(s)

1 School of Medical Technology, Hebei Medical University, Shijiazhuang, Hebei, China

Corresponding Author

Haiyang Yan

ABSTRACT

Persistent infection with Hepatitis B virus (HBV) for more than six months can lead to chronic hepatitis B (CHB), which is a major cause of Hepatocellular carcinoma (HCC). Chronic HBV infection continuously damages the liver and promotes the formation of an immunosuppressive and inflammatory hepatic microenvironment, but the mechanisms linking hepatocyte alterations to immune dysfunction during disease progression remain incompletely understood. This review focuses on how chronic HBV infection reprograms hepatocytes and reshapes the hepatic immune microenvironment during the transition from CHB to HCC. We propose that epigenetic alterations and metabolic rewiring are two interconnected mechanisms driving this process. These changes regulate gene expression, signaling pathways, and metabolite production in hepatocytes, thereby influencing cytokine and metabolite release that promotes immune cell dysfunction and immune suppression. Overall, we highlights the mechanistic connection between hepatocyte reprogramming and immune microenvironment remodeling in HBV-related hepatocarcinogenesis, and discusses potential therapeutic targets for HBV-associated HCC. 

KEYWORDS

Tumor Microenvironment, Hepatitis B virus, Hepatocellular Carcinoma, Cytokines

CITE THIS PAPER

Jiaxiang Li, Haiyang Yan. Hepatitis B-Induced Immunological Remodeling in Hepatocellular Carcinoma. MEDS Clinical Medicine (2026). Vol. 7, No.2, 71-82. DOI: http://dx.doi.org/10.23977/medsc.2026.070210.

REFERENCES

[1] Hsu, Y.C., Huang, D.Q. and Nguyen, M.H. (2023) Global Burden of Hepatitis B Virus: Current Status, Missed Opportunities and a Call for Action. Nature Reviews Gastroenterology & Hepatology, 20, 524-537.
[2] Zheng, Y.F., Lu, X.J., Zhang, X.Y. and Guan, B.G. (2019) The Landscape of DNA Methylation in Hepatocellular Carcinoma. Journal of Cellular Physiology, 234, 2631-2638.
[3] Udali, S., Guarini, P., Ruzzenente, A., Ferrarini, A., Guglielmi, A., Lotto, V., Tononi, P., Pattini, P., Moruzzi, S., Campagnaro, T., Conci, S., Olivieri, O., Corrocher, R., Delledonne, M., Choi, S.W. and Friso, S. (2015) DNA Methylation and Gene Expression Profiles Show Novel Regulatory Pathways in Hepatocellular Carcinoma. Clinical Epigenetics, 7, 13.
[4] Zhang, C., Huang, C.X., Sui, X.B., Zhong, X.Q., Yang, W.J., Hu, X.R. and Li, Y.Q. (2019) Association between Gene Methylation and Hbv Infection in Hepatocellular Carcinoma: A Meta-Analysis. Journal of Cancer, 10, 6457-6465.
[5] Koumbi, L. and Karayiannis, P. (2016) The Epigenetic Control of Hepatitis B Virus Modulates the Outcome of Infection. Frontiers in Microbiology, 6, 9.
[6] Villanueva, A., Portela, A., Sayols, S., Battiston, C., Hoshida, Y., Méndez-González, J., Imbeaud, S., Letouzé, E., Hernandez-Gea, V., Cornella, H., Pinyol, R., Solé, M., Fuster, J., Zucman-Rossi, J., Mazzaferro, V., Esteller, M., Llovet, J.M. and Consortium, H. (2015) DNA Methylation-Based Prognosis and Epidrivers in Hepatocellular Carcinoma. Hepatology, 61, 1945-1956.
[7] Garmpis, N., Damaskos, C., Garmpi, A., Georgakopoulou, V.E., Sarantis, P., Antoniou, E.A., Karamouzis, M.V., Nonni, A., Schizas, D., Diamantis, E., Koustas, E., Farmaki, P., Syllaios, A., Patsouras, A., Kontzoglou, K., Trakas, N. and Dimitroulis, D. (2021) Histone Deacetylase Inhibitors in the Treatment of Hepatocellular Carcinoma: Current Evidence and Future Opportunities. Journal of Personalized Medicine, 11, 15.
[8] Xu, J., Guan, X.Y., Jia, X.D., Li, H.Y., Chen, R.B. and Lu, Y.Y. (2022) In-Depth Profiling and Quantification of the Lysine Acetylome in Hepatocellular Carcinoma with a Trapped Ion Mobility Mass Spectrometer. Molecular & Cellular Proteomics, 21, 19.
[9] Xia, J.K., Qin, X.Q., Zhang, L., Liu, S.J., Shi, X.L. and Ren, H.Z. (2022) Roles and Regulation of Histone Acetylation in Hepatocellular Carcinoma. Frontiers in Genetics, 13, 12.
[10] Xu, Y.Y., Liao, W., Luo, Q., Yang, D.H. and Pan, M.X. (2022) Histone Acetylation Regulator-Mediated Acetylation Patterns Define Tumor Malignant Pathways and Tumor Microenvironment in Hepatocellular Carcinoma. Frontiers in Immunology, 13, 19.
[11] Tian, Z.L., Xu, C., He, W.X., Lin, Z.B., Zhang, W.J., Tao, K.S., Ding, R., Zhang, X. and Dou, K.F. (2023) The Deubiquitinating Enzyme Usp19 Facilitates Hepatocellular Carcinoma Progression through Stabilizing Yap. Cancer Letters, 577, 12.
[12] Ma, M.R., Yi, L., Pei, Y.F., Zhang, Q.M., Tong, C., Zhao, M.Y., Chen, Y.H., Zhu, J.H., Zhang, W.G., Yao, F., Yang, P.Y. and Zhang, P.J. (2024) Usp26 as a Hepatitis B Virus-Induced Deubiquitinase Primes Hepatocellular Carcinogenesis by Epigenetic Remodeling. Nature Communications, 15, 18.
[13] Zhao, J.N., Li, Y.X., Zhu, J., Li, H. and Jin, X.F. (2025) Ubiquitination in Hepatocellular Carcinoma Immunity. Journal of Translational Medicine, 23, 17.
[14] Wang, H.L., Li, Q., Tang, Q.Q., Shi, G., Wu, G., Mao, X.B., Wu, C.K., Zhang, L.X., Liu, J., Li, J.D. and Li, B. (2024) Role and Therapeutic Potential of E3s in the Tumor Microenvironment of Hepatocellular Carcinoma. Frontiers in Immunology, 15, 8.
[15] Zuo, Q.Z., He, J., Zhang, S., Wang, H., Jin, G.Z., Jin, H.J., Cheng, Z.A., Tao, X.M., Yu, C.T., Li, B.T., Yang, C., Wang, S.Y., Lv, Y.Y., Zhao, F.Y., Yao, M., Cong, W.M., Wang, C. and Qin, W.X. (2021) Pparγ Coactivator-1α Suppresses Metastasis of Hepatocellular Carcinoma by Inhibiting Warburg Effect by Pparγ-Dependent Wnt/Β-Catenin/Pyruvate Dehydrogenase Kinase Isozyme 1 Axis. Hepatology, 73, 644-660.
[16] Lu, C.Y., Fang, S.J., Weng, Q.Y., Lv, X.L., Meng, M.M., Zhu, J.Y., Zheng, L.Y., Hu, Y.M., Gao, Y., Wu, X.L., Mao, J.T., Tang, B.F., Zhao, Z.W., Huang, L. and Ji, J.S. (2020) Integrated Analysis Reveals Critical Glycolytic Regulators in Hepatocellular Carcinoma. Cell Communication and Signaling, 18, 14.
[17] An, L.B. and Li, Z.F. (2025) Molecular Network of Metabolic Reprogramming and Precision Diagnosis and Treatment of Hepatocellular Carcinoma. Biomarker Research, 13, 32.
[18] Mossenta, M., Busato, D., Dal Bo, M. and Toffoli, G. (2020) Glucose Metabolism and Oxidative Stress in Hepatocellular Carcinoma: Role and Possible Implications in Novel Therapeutic Strategies. Cancers, 12, 30.
[19] Park, S. and Hall, M.N. (2025) Metabolic Reprogramming in Hepatocellular Carcinoma: Mechanisms and Therapeutic Implications. Experimental and Molecular Medicine, 57, 515-523.
[20] Zhou, F.L. and Sun, X.L. (2021) Cholesterol Metabolism: A Double-Edged Sword in Hepatocellular Carcinoma. Frontiers in Cell and Developmental Biology, 9, 10.
[21] Dai, P., Feng, J., Dong, Y.Y., Zhang, S.J., Cao, J.H., Cui, X.P., Qin, X.L., Yang, S.M. and Fan, D.G. (2025) Metabolic Reprogramming in Hepatocellular Carcinoma: An Integrated Omics Study of Lipid Pathways and Their Diagnostic Potential. Journal of Translational Medicine, 23, 17.
[22] Li, Y., Mo, H.Y., Jia, S.Y., Wang, J., Ma, Y., Liu, X. and Tu, K.S. (2022) Comprehensive Analysis of the Amino Acid Metabolism-Related Gene Signature for Prognosis, Tumor Immune Microenvironment, and Candidate Drugs in Hepatocellular Carcinoma. Frontiers in Immunology, 13, 18.
[23] Ye, Y.Y., Yu, B.D., Wang, H. and Yi, F.M. (2023) Glutamine Metabolic Reprogramming in Hepatocellular Carcinoma. Frontiers in Molecular Biosciences, 10, 13.
[24] Gao, B.C., Lu, Y., Lai, X.Y., Xu, X., Gou, S.H., Yang, Z.D., Gong, Y.J. and Yang, H. (2025) Metabolic Reprogramming in Hepatocellular Carcinoma: Mechanisms of Immune Evasion and Therapeutic Implications. Frontiers in Immunology, 16, 8.
[25] Morine, Y., Utsunomiya, T., Yamanaka-Okumura, H., Saito, Y., Yamada, S., Ikemoto, T., Imura, S., Kinoshita, S., Hirayama, A. and Tanaka, Y. (2022) Essential Amino Acids as Diagnostic Biomarkers of Hepatocellular Carcinoma Based on Metabolic Analysis. Oncotarget, 13, 1286-1298.
[26] Cervantes, A., Daniele, B. and Martinelli, E. (2021) Hepatocellular Carcinoma. Nature Reviews Disease Primers, 7, 1.
[27] Ringelhan, M., Pfister, D., O'Connor, T., Pikarsky, E. and Heikenwalder, M. (2018) The Immunology of Hepatocellular Carcinoma. Nature Immunology, 19, 222-232.
[28] Wan, S.S., Zhao, E.D., Kryczek, I., Vatan, L., Sadovskaya, A., Ludema, G., Simeone, D.M., Zou, W.P. and Welling, T.H. (2014) Tumor-Associated Macrophages Produce Interleukin 6 and Signal Via Stat3 to Promote Expansion of Human Hepatocellular Carcinoma Stem Cells. Gastroenterology, 147, 1393-1404.
[29] Bergmann, J., Müller, M., Baumann, N., Reichert, M., Heneweer, C., Bolik, J., Lücke, K., Gruber, S., Carambia, A., Boretius, S., Leuschner, I., Becker, T., Rabe, B., Herkel, J., Wunderlich, F.T., Mittrücker, H.W., Rose-John, S. and Schmidt-Arras, D. (2017) Il-6 Trans-Signaling Is Essential for the Development of Hepatocellular Carcinoma in Mice. Hepatology, 65, 89-103.
[30] Zhou, M., Yang, H., Learned, R.M., Tian, H. and Ling, L. (2017) Non-Cell-Autonomous Activation of Il-6/Stat3 Signaling Mediates Fgf19-Driven Hepatocarcinogenesis. Nature Communications, 8, 16.
[31] Jiang, J., Wang, G.Z., Wang, Y., Huang, H.Z., Li, W.T. and Qu, X.D. (2018) Hypoxia-Induced Hmgb1 Expression of Hcc Promotes Tumor Invasiveness and Metastasis Via Regulating Macrophage-Derived Il-6. Experimental Cell Research, 367, 81-88.
[32] Sun, C., Sun, H.Y., Zhang, C. and Tian, Z.G. (2015) Nk Cell Receptor Imbalance and Nk Cell Dysfunction in Hbv Infection and Hepatocellular Carcinoma. Cellular & Molecular Immunology, 12, 292-302.
[33] Jin, X.M. and Bi, J.C. (2022) Prospects for Nk-Based Immunotherapy of Chronic Hbv Infection. Frontiers in Immunology, 13, 10.
[34] Sung, P.S. and Jang, J.W. (2018) Natural Killer Cell Dysfunction in Hepatocellular Carcinoma: Pathogenesis and Clinical Implications. International Journal of Molecular Sciences, 19, 23.
[35] Sun, C., Sun, H.Y., Xiao, W.H., Zhang, C. and Tian, Z.G. (2015) Natural Killer Cell Dysfunction in Hepatocellular Carcinoma and Nk Cell-Based Immunotherapy. Acta Pharmacologica Sinica, 36, 1191-1199.
[36] Yonejima, A., Mizukoshi, E., Tamai, T., Nakagawa, H., Kitahara, M., Yamashita, T., Arai, K., Terashima, T., Iida, N., Fushimi, K., Okada, H., Yamashita, T., Sakai, Y., Honda, M. and Kaneko, S. (2019) Characteristics of Impaired Dendritic Cell Function in Patients with Hepatitis B Virus Infection. Hepatology, 70, 25-39.
[37] Li, W.Y., Chen, G.J., Peng, H.L., Zhang, Q.F., Nie, D.Y., Guo, T., Zhu, Y.X., Zhang, Y.H. and Lin, M. (2024) Research Progress on Dendritic Cells in Hepatocellular Carcinoma Immune Microenvironments. Biomolecules, 14, 16.
[38] Ying, S.D., Liu, H.Y., Zhang, Y.L. and Mei, Y. (2025) Harnessing Dendritic Cell Function in Hepatocellular Carcinoma: Advances in Immunotherapy and Therapeutic Strategies. Vaccines, 13, 23.
[39] Zhao, H.J., Yu, Y.T., Wang, Y.C., Zhao, L.H., Yang, A.L., Hu, Y.F., Pan, Z.Y., Wang, Z.X., Yang, J.R., Han, Q.J., Tian, Z.G. and Zhang, J. (2022) Cholesterol Accumulation on Dendritic Cells Reverses Chronic Hepatitis B Virus Infection-Induced Dysfunction. Cellular & Molecular Immunology, 19, 1347-1360.
[40] Cheng, Y., Gunasegaran, B., Singh, H.D., Dutertre, C.A., Loh, C.Y., Lim, J.Q., Crawford, J.C., Lee, H.K., Zhang, X.M., Lee, B., Becht, E., Lim, W.J., Yeong, J., Chan, C.Y., Chung, A., Goh, B.K.P., Chow, P.K.H., Chan, J.K.Y., Ginhoux, F., Tai, D., Chen, J.M., Lim, S.G., Zhai, W., Choo, S.P. and Newell, E.W. (2021) Non-Terminally Exhausted Tumor-Resident Memory Hbv-Specific T Cell Responses Correlate with Relapse-Free Survival in Hepatocellular Carcinoma. Immunity, 54, 1825-1841.
[41] Hao, X.L., Chen, Y.Y., Bai, L., Wei, H.M., Sun, R. and Tian, Z.G. (2021) Hbsag-Specific Cd8+ T Cells as an Indispensable Trigger to Induce Murine Hepatocellular Carcinoma. Cellular & Molecular Immunology, 18, 128-137.
[42] Liu, L.L., Liu, J.W., Li, P., Luo, J.J., Qin, R., Peng, Q., Li, B., Wei, X.Y., Wang, T., Shi, H.Y., Wang, M.D., Li, C., Fang, W.J., Chen, W., Xu, X., Yang, T., Yin, W.W. and Zeng, X. (2023) Single-Cell Analysis Reveals Hbv-Specific Pd-1+Cd8+ Trm Cells in Tumor Borders Are Associated with Hbv-Related Hepatic Damage and Fibrosis in Hcc Patients. Journal of Experimental & Clinical Cancer Research, 42, 17.
[43] Cho, H.J. and Cheong, J.Y. (2021) Role of Immune Cells in Patients with Hepatitis B Virus-Related Hepatocellular Carcinoma. International Journal of Molecular Sciences, 22, 12.
[44] Gao, Y.N., Zhang, Z.X., Huang, X.T., You, M.J., Du, C.Z., Li, N., Hao, Y.J., Wang, K., Ding, X., Yang, F.Q., Cheng, S.Q., Luo, J.J., Chen, R.S. and Yang, P.Y. (2025) Hbv-Associated Hepatocellular Carcinomas Inhibit Antitumor Cd8+ T Cell Via the Long Noncoding Rna Hdac2-As2. Nature Communications, 16, 18.
[45] Zhang, J., Hu, C.W., Xie, X.X., Qi, L.Z., Li, C.Z. and Li, S.Z. (2023) Immune Checkpoint Inhibitors in Hbv-Caused Hepatocellular Carcinoma Therapy. Vaccines, 11, 21.
[46] Broholm, M., Mathiasen, A.S., Apol, A.D. and Weis, N. (2024) The Adaptive Immune Response in Hepatitis B Virus-Associated Hepatocellular Carcinoma Is Characterized by Dysfunctional and Exhausted Hbv-Specific T Cells. Viruses-Basel, 16, 14.
[47] Wang, S., Meng, L.J., Xu, N., Chen, H., Xiao, Z.F., Lu, D., Fan, X.H., Xia, L.M., Chen, J., Zheng, S.S., Wei, Q., Wei, X.Y. and Xu, X. (2024) Hepatocellular Carcinoma-Specific Epigenetic Checkpoints Bidirectionally Regulate the Antitumor Immunity of Cd4+T Cells. Cellular & Molecular Immunology, 21, 1296-1308.
[48] Venzin, V., Beccaria, C.G., Perucchini, C., Delfino, P., Bono, E.B., Giustini, L., Moalli, F., Grillo, M., Fumagalli, V., Laura, C., Di Lucia, P., Reinhard, K., Petschenka, J., Omokoko, T.A., Celant, A., Ottolini, S., Kawashima, K., Rava, M., De Giovanni, M., Inverso, D., Kuka, M., Kennedy, P.T.F., Guilliams, M., Casorati, G., Pedica, F., Ponzoni, M., Sahin, U., Le Bert, N., Bertoletti, A., Vascotto, F., Guidotti, L.G. and Iannacone, M. (2025) Cd4+ T Cells License Kupffer Cells to Reverse Cd8+ T Cell Dysfunction Induced by Hepatocellular Priming. Nature Immunology, 26, 40.
[49] Khlaiphuengsin, A., Chuaypen, N., Sodsai, P., Buranapraditkun, S., Boonpiyathad, T., Hirankarn, N. and Tangkijvanich, P. (2020) Decreased of Baff-R Expression and B Cells Maturation in Patients with Hepatitis B Virus-Related Hepatocellular Carcinoma. World Journal of Gastroenterology, 26, 13.
[50] Zhang, Z., Ma, L.J., Goswami, S., Ma, J.Q., Zheng, B.H., Duan, M., Liu, L.Z., Zhang, L.J., Shi, J.Y., Dong, L.Q., Sun, Y.M., Tian, L.Y., Gao, Q. and Zhang, X.M. (2019) Landscape of Infiltrating B Cells and Their Clinical Significance in Human Hepatocellular Carcinoma. Oncoimmunology, 8, 11.
[51] Garnelo, M., Tan, A., Her, Z.S., Yeong, J., Lim, C.J., Chen, J.M., Lim, K.H., Weber, A., Chow, P., Chung, A., Ooi, L.L.P., Toh, H.C., Heikenwalder, M., Ng, I.O.L., Nardin, A., Chen, Q.F., Abastado, J.P. and Chew, V. (2017) Interaction between Tumour-Infiltrating B Cells and T Cells Controls the Progression of Hepatocellular Carcinoma. Gut, 66, 342-351.
[52] Liu, X., Liu, Z.L., Zhu, C.Z., Kobayashi, T., Lei, P.J., Shi, Y., Yuan, D.D., Wang, J.G., Li, M., Matsui, A., Mafra, K., Ando, T., Kojo, K., Schleinhege, R., Miyazaki, K., Huang, P.G., Kuang, M., Bod, L. and Duda, D.G. (2025) Inhibiting B Cells Enhances the Efficacy of Sting Agonism or Immune Checkpoint Blockade in Hepatocellular Carcinoma. Nature Communications, 16, 17.

Subscription
E-Mail Alert
Most popular papers
Call for Special Issue
Publication Ethics & OA Statement
Plagiarism Policy
Contact Us
Downloads: 11561
Visits: 966416

Sponsors, Associates, and Links

All published work is licensed under a Creative Commons Attribution 4.0 International License.

Copyright © 2016 - 2031 Clausius Scientific Press Inc. All Rights Reserved.