Immunotherapy for hepatocellular carcinoma

Abstract

As the third leading cause of cancer-related mortality worldwide, hepatocellular carcinoma (HCC) constitutes a substantial global health burden. Immunotherapy has transformed HCC management, encompassing immune checkpoint inhibitors, cytokine-based therapies, adoptive cell therapies, and oncolytic viruses. Clinical research is increasingly focused on combination immunotherapy, which offers improved treatment prospects, particularly for patients with unresectable HCC. This review provides a concise overview of the HCC immune microenvironment, emphasizing the role of immune cells in HCC pathogenesis and progression. Additionally, it examines the molecular mechanisms underlying HCC immunotherapy, summarizes relevant clinical trials and their outcomes, discusses key therapeutic agents and combination strategies, and addresses current challenges and future directions in the field.

Keywords

Hepatocellular carcinoma / Immunotherapy / Immune checkpoint inhibitor / Combination therapy / Medical and Health Sciences / Immunology

References

[1] Sung, H., J. Ferlay, R.L. Siegel, 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(3):209–249.https://doi.org/10.3322/caac.21660

[2] Ferlay, J., M. Colombet, I. Soerjomataram, et al., Cancer statistics for the year 2020: An overview. Int J Cancer. 2021.https://doi.org/10.1002/ijc.33588

[3] Vogel, A., T. Meyer, G. Sapisochin, et al., Hepatocellular carcinoma. Lancet. 2022. 400(10360):1345–1362.https://doi.org/10.1016/s0140-6736(22)01200-4

[4] Ko, K.P., A. Shin, S. Cho, et al., Environmental contributions to gastrointestinal and liver cancer in the Asia-Pacific region. J Gastroenterol Hepatol. 2018. 33(1):111–120.https://doi.org/10.1111/jgh.14005

[5] Koshy, A., Evolving Global Etiology of Hepatocellular Carcinoma (HCC): Insights and Trends for 2024. J Clin Exp Hepatol. 2025. 15(1):102406.https://doi.org/10.1016/j.jceh.2024.102406

[6] Zeng, H., R. Zheng, K. Sun, et al., Cancer survival statistics in China 2019–2021: a multicenter, population-based study. J Natl Cancer Cent. 2024. 4(3):203–213.https://doi.org/10.1016/j.jncc.2024.06.005

[7] Tilg, H., T.E. Adolph and F. Tacke, Therapeutic modulation of the liver immune microenvironment. Hepatol. 2023. 78(5):1581–1601.https://doi.org/10.1097/hep.0000000000000386

[8] Liu, Y., H. Yang, T. Li, et al., Immunotherapy in liver cancer: overcoming the tolerogenic liver microenvironment. Front Immunol. 2024. 15:1460282.https://doi.org/10.3389/fimmu.2024.1460282

[9] Kubes, P. and C. Jenne, Immune Responses in the Liver. Annu Rev Immunol. 2018. 36:247–277.https://doi.org/10.1146/annurev-immunol-051116-052415

[10] Horst, A.K., K. Neumann, L. Diehl, et al., Modulation of liver tolerance by conventional and nonconventional antigen-presenting cells and regulatory immune cells. Cell Mol Immunol. 2016. 13(3):277–92.https://doi.org/10.1038/cmi.2015.112

[11] Wang, K., P. Coutifaris, D. Brocks, et al., Combination anti-PD-1 and anti-CTLA-4 therapy generates waves of clonal responses that include progenitor-exhausted CD8(+) T cells. Cancer Cell. 2024. 42(9):1582–1597.e10.https://doi.org/10.1016/j.ccell.2024.08.007

[12] Briukhovetska, D., J. Dörr, S. Endres, et al., Interleukins in cancer: from biology to therapy. Nat Rev Cancer. 2021. 21(8):481–499.https://doi.org/10.1038/s41568-021-00363-z

[13] Propper, D.J. and F.R. Balkwill, Harnessing cytokines and chemokines for cancer therapy. Nat Rev Clin Oncol. 2022. 19(4):237–253.https://doi.org/10.1038/s41571-021-00588-9

[14] Kruger, S., M. Ilmer, S. Kobold, et al., Advances in cancer immunotherapy 2019 - latest trends. J Exp Clin Cancer Res. 2019. 38(1):268.https://doi.org/10.1186/s13046-019-1266-0

[15] Elia, G., S.M. Ferrari, M.R. Galdiero, et al., New insight in endocrine-related adverse events associated to immune checkpoint blockade. Best Pract Res Clin Endocrinol Metab. 2020. 34(1):101370.https://doi.org/10.1016/j.beem.2019.101370

[16] Sharma, P., S. Goswami, D. Raychaudhuri, et al., Immune checkpoint therapy-current perspectives and future directions. Cell. 2023. 186(8):1652–1669.https://doi.org/10.1016/j.cell.2023.03.006

[17] Freeman, G.J., A.J. Long, Y. Iwai, et al., Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000. 192(7):1027–34.https://doi.org/10.1084/jem.192.7.1027

[18] Ishida, Y., Y. Agata, K. Shibahara, et al., Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. Embo j. 1992. 11(11):3887–95.https://doi.org/10.1002/j.1460-2075.1992.tb05481.x

[19] Topalian, S.L., J.M. Taube, R.A. Anders, et al., Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer. 2016. 16(5):275–87.https://doi.org/10.1038/nrc.2016.36

[20] Tang, H., Y. Liang, R.A. Anders, et al., PD-L1 on host cells is essential for PD-L1 blockade-mediated tumor regression. J Clin Invest. 2018. 128(2):580–588.https://doi.org/10.1172/jci96061

[21] Marasco, M., A. Berteotti, J. Weyershaeuser, et al., Molecular mechanism of SHP2 activation by PD-1 stimulation. Sci Adv. 2020. 6(5):eaay4458.https://doi.org/10.1126/sciadv.aay4458

[22] Patsoukis, N., J.S. Duke-Cohan, A. Chaudhri, et al., Interaction of SHP-2 SH2 domains with PD-1 ITSM induces PD-1 dimerization and SHP-2 activation. Commun Biol. 2020. 3(1):128.https://doi.org/10.1038/s42003-020-0845-0

[23] Hui, E., J. Cheung, J. Zhu, et al., T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science. 2017. 355(6332):1428–1433.https://doi.org/10.1126/science.aaf1292

[24] Cai, J., D. Wang, G. Zhang, et al., The Role Of PD-1/PD-L1 Axis In Treg Development And Function: Implications For Cancer Immunotherapy. Onco Targets Ther. 2019. 12:8437–8445.https://doi.org/10.2147/ott.S221340

[25] Daassi, D., K.M. Mahoney and G.J. Freeman, The importance of exosomal PDL1 in tumour immune evasion. Nat Rev Immunol. 2020. 20(4):209–215.https://doi.org/10.1038/s41577-019-0264-y

[26] Kuzume, A., S. Chi, N. Yamauchi, et al., Immune-Checkpoint Blockade Therapy in Lymphoma. Int J Mol Sci. 2020. 21(15).https://doi.org/10.3390/ijms21155456

[27] Vignali, D.A., L.W. Collison and C.J. Workman, How regulatory T cells work. Nat Rev Immunol. 2008. 8(7):523–32.https://doi.org/10.1038/nri2343

[28] Wing, K., Y. Onishi, P. Prieto-Martin, et al., CTLA-4 control over Foxp3+ regulatory T cell function. Science. 2008. 322(5899):271–5.https://doi.org/10.1126/science.1160062

[29] Chen, L., Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nat Rev Immunol. 2004. 4(5):336–47.https://doi.org/10.1038/nri1349

[30] Buchan, S.L., CTLA-4: Checkpoints beyond the membrane. Mol Ther. 2024. 32(2):279–281.https://doi.org/10.1016/j.ymthe.2024.01.002

[31] Dixon, K.O., G.F. Lahore and V.K. Kuchroo, Beyond T cell exhaustion: TIM-3 regulation of myeloid cells. Sci Immunol. 2024. 9(93):eadf2223.https://doi.org/10.1126/sciimmunol.adf2223

[32] Cazzato, G., E. Cascardi, A. Colagrande, et al., T Cell Immunoglobulin and Mucin Domain 3 (TIM-3) in Cutaneous Melanoma: A Narrative Review. Cancers (Basel). 2023. 15(6).https://doi.org/10.3390/cancers15061697

[33] Banerjee, H., H. Nieves-Rosado, A. Kulkarni, et al., Expression of Tim-3 drives phenotypic and functional changes in Treg cells in secondary lymphoid organs and the tumor microenvironment. Cell Rep. 2021. 36(11):109699.https://doi.org/10.1016/j.celrep.2021.109699

[34] Triebel, F., S. Jitsukawa, E. Baixeras, et al., LAG-3, a novel lymphocyte activation gene closely related to CD4. J Exp Med. 1990. 171(5):1393–405.https://doi.org/10.1084/jem.171.5.1393

[35] Prigent, P., S. El Mir, M. Dréano, et al., Lymphocyte activation gene-3 induces tumor regression and antitumor immune responses. Eur J Immunol. 1999. 29(12):3867–76.https://doi.org/10.1002/(sici)1521-4141(199912)29:12<3867::Aid-immu3867>3.0.Co;2-e

[36] Liang, B., C. Workman, J. Lee, et al., Regulatory T cells inhibit dendritic cells by lymphocyte activation gene-3 engagement of MHC class II. J Immunol. 2008. 180(9):5916–26.https://doi.org/10.4049/jimmunol.180.9.5916

[37] Yu, X., K. Harden, L.C. Gonzalez, et al., The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells. Nat Immunol. 2009. 10(1):48–57.https://doi.org/10.1038/ni.1674

[38] Ge, Z., M.P. Peppelenbosch, D. Sprengers, et al., TIGIT, the Next Step Towards Successful Combination Immune Checkpoint Therapy in Cancer. Front Immunol. 2021. 12:699895.https://doi.org/10.3389/fimmu.2021.699895

[39] Gur, C., Y. Ibrahim, B. Isaacson, et al., Binding of the Fap2 protein of Fusobacterium nucleatum to human inhibitory receptor TIGIT protects tumors from immune cell attack. Immunity. 2015. 42(2):344–355.https://doi.org/10.1016/j.immuni.2015.01.010

[40] Akdis, M., S. Burgler, R. Crameri, et al., Interleukins, from 1 to 37, and interferon-γ: receptors, functions, and roles in diseases. J Allergy Clin Immunol. 2011. 127(3):701–21.e1–70.https://doi.org/10.1016/j.jaci.2010.11.050

[41] Shalapour, S. and M. Karin, Pas de Deux: Control of Anti-tumor Immunity by Cancer-Associated Inflammation. Immunity. 2019. 51(1):15–26.https://doi.org/10.1016/j.immuni.2019.06.021

[42] Liao, Z., H. Zhang, F. Liu, et al., m(6)A-Dependent ITIH1 Regulated by TGF-β Acts as a Target for Hepatocellular Carcinoma Progression. Adv Sci (Weinh). 2024. 11(42):e2401013.https://doi.org/10.1002/advs.202401013

[43] Llovet, J.M., F. Castet, M. Heikenwalder, et al., Immunotherapies for hepatocellular carcinoma. Nat Rev Clin Oncol. 2022. 19(3):151–172.https://doi.org/10.1038/s41571-021-00573-2

[44] Melero, I., T. Yau, Y.K. Kang, et al., Nivolumab plus ipilimumab combination therapy in patients with advanced hepatocellular carcinoma previously treated with sorafenib: 5-year results from CheckMate 040. Ann Oncol. 2024. 35(6):537–548.https://doi.org/10.1016/j.annonc.2024.03.005

[45] El-Khoueiry, A.B., B. Sangro, T. Yau, et al., Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017. 389(10088):2492–2502.https://doi.org/10.1016/s0140-6736(17)31046-2

[46] Yau, T., J.W. Park, R.S. Finn, et al., Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2022. 23(1):77–90.https://doi.org/10.1016/s1470-2045(21)00604-5

[47] Zhu, A.X., R.S. Finn, J. Edeline, et al., Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018. 19(7):940–952.https://doi.org/10.1016/s1470-2045(18)30351-6

[48] Finn., R.S., K. Gu., P.M. Xi Chen, et al., Second-line pembrolizumab for advanced HCC: meta-analysis of the phase 3 KEYNOTE-240 and KEYNOTE-394 studies. JHEP reports. 2025–02–01.https://doi.org/10.1016/j.jhepr.2025.101350

[49] Finn, R.S., B.Y. Ryoo, P. Merle, et al., Pembrolizumab As Second-Line Therapy in Patients With Advanced Hepatocellular Carcinoma in KEYNOTE-240: A Randomized, Double-Blind, Phase III Trial. J Clin Oncol. 2020. 38(3):193–202.https://doi.org/10.1200/jco.19.01307

[50] Qin, S., Z. Chen, W. Fang, et al., Pembrolizumab Versus Placebo as Second-Line Therapy in Patients From Asia With Advanced Hepatocellular Carcinoma: A Randomized, Double-Blind, Phase III Trial. J Clin Oncol. 2023. 41(7):1434–1443.https://doi.org/10.1200/jco.22.00620

[51] Ren, Z., M. Ducreux, G.K. Abou-Alfa, et al., Tislelizumab in Patients with Previously Treated Advanced Hepatocellular Carcinoma (RATIONALE-208): A Multicenter, Non-Randomized, Open-Label, Phase 2 Trial. Liver Cancer. 2023. 12(1):72–84.https://doi.org/10.1159/000527175

[52] Qin, S., M. Kudo, T. Meyer, et al., Tislelizumab vs Sorafenib as First-Line Treatment for Unresectable Hepatocellular Carcinoma: A Phase 3 Randomized Clinical Trial. JAMA Oncol. 2023. 9(12):1651–1659.https://doi.org/10.1001/jamaoncol.2023.4003

[53] Qin, S., R.S. Finn, M. Kudo, et al., RATIONALE 301 study: tislelizumab versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma. Future Oncol. 2019. 15(16):1811–1822.https://doi.org/10.2217/fon-2019-0097

[54] al, R.S.H.F.d.M.G.G.A.V.C.H.B.e., IMpower110: Updated OS Analysis of Atezolizumab vs Platinum-Based Chemotherapy as First-Line Treatment in PD-L1–Selected NSCLC. J Thoracic Oncol. 2021–03–01.https://doi.org/10.1016/j.jtho.2021.01.142

[55] Sangro, B., S.L. Chan, R.K. Kelley, et al., Four-year overall survival update from the phase III HIMALAYA study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. Ann Oncol. 2024. 35(5):448–457.https://doi.org/10.1016/j.annonc.2024.02.005

[56] Sangro, B., C. Gomez-Martin, M. de la Mata, et al., A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepatol. 2013. 59(1):81–8.https://doi.org/10.1016/j.jhep.2013.02.022

[57] Wang X, Lu L. Immunotherapy for hepatocellular carcinoma. Chin Med J (Engl). 2024;137(15):1765–76. https://doi.org/10.1097/cm9.0000000000003060.

[58] Ren, Z., Y. Guo, Y. Bai, et al., Tebotelimab, a PD-1/LAG-3 bispecific antibody, in patients with advanced hepatocellular carcinoma who had failed prior targeted therapy and/or immunotherapy: An open-label, single-arm, phase 1/2 dose-escalation and expansion study. J Clin Oncol. 2023;41(4_suppl):578–578.

[59] Ren Z, H.Y., Guo Y, et al. , 945MO AdvanTIG-206: Phase II randomized open-label study of ociperlimab(OCI)+tislelizumab(TIS)+BAT1706(bevacizumab biosimilar)versus TIS+BAT1706 in patients(pts)with advanced hepatocellular carcinoma(HCC). Ann Oncol. 2023.

[60] Finn, R.S., B.Y. Ryoo, C.H. Hsu, et al., Tiragolumab in combination with atezolizumab and bevacizumab in patients with unresectable, locally advanced or metastatic hepatocellular carcinoma (MORPHEUS-Liver): a randomised, open-label, phase 1b-2, study. Lancet Oncol. 2025. 26(2):214–226.https://doi.org/10.1016/s1470-2045(24)00679-x

[61] Kelley RK, Sangro B, Harris W, et al. Safety, efficacy, and pharmacodynamics of tremelimumab plus durvalumab for patients with unresectable hepatocellular carcinoma: randomized expansion of a phase I/II study. J Clin Oncol. 2021. 39(27):2991–3001. https://doi.org/10.1200/jco.20.03555.

[62] Galle, P.R., T. Decaens, M. Kudo, et al., Nivolumab (NIVO) plus ipilimumab (IPI) vs lenvatinib (LEN) or sorafenib (SOR) as first-line treatment for unresectable hepatocellular carcinoma (uHCC): First results from CheckMate 9DW. J Clin Oncol. 2024. 42(17_suppl):LBA4008-LBA4008.

[63] Semela, D. and J.F. Dufour, Angiogenesis and hepatocellular carcinoma. J Hepatol. 2004. 41(5):864–80.https://doi.org/10.1016/j.jhep.2004.09.006

[64] Ren, Z., J. Xu, Y. Bai, et al., Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2–3 study. Lancet Oncol. 2021;22(7):977–90. https://doi.org/10.1016/s1470-2045(21)00252-7

[65] Hilmi, M., C. Neuzillet, J. Calderaro, et al., Angiogenesis and immune checkpoint inhibitors as therapies for hepatocellular carcinoma: current knowledge and future research directions. J Immunother Cancer. 2019. 7(1):333.https://doi.org/10.1186/s40425-019-0824-5

[66] Finn, R.S., S. Qin, M. Ikeda, et al., Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020. 382(20):1894–1905.https://doi.org/10.1056/NEJMoa1915745

[67] Ren, Z., J. Xu, Y. Bai, et al., Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2–3 study. The Lancet Oncol. 2021: 977-990.

[68] Xu, J., Y. Zhang, G. Wang, et al., SCT-I10A combined with a bevacizumab biosimilar (SCT510) versus sorafenib in the first-line treatment of advanced hepatocellular carcinoma: A randomized phase 3 trial. J Clin Oncol. 2024. 42(16_suppl):4092–4092.

[69] QinS, FanJ, YangF, et al. . LBA38 Iparomlimab and tuvonralimab (QL1706) with bevacizumab and/or chemotherapy in first-line (1L) treatment of advanced hepatocellular carcinoma (aHCC): A randomized, open-label, phase II/III study (DUBHE-H-308). Ann Oncol, 2024, 35Sup22

[70] Olsson, A.K., A. Dimberg, J. Kreuger, et al., VEGF receptor signalling - in control of vascular function. Nat Rev Mol Cell Biol. 2006. 7(5):359–71.https://doi.org/10.1038/nrm1911

[71] Huang, X., L. Xu, T. Ma, et al., Lenvatinib Plus Immune Checkpoint Inhibitors Improve Survival in Advanced Hepatocellular Carcinoma: A Retrospective Study. Front Oncol. 2021. 11: p. 751159.https://doi.org/10.3389/fonc.2021.751159

[72] Kudo, M., M. Ikeda, K. Motomura, et al., A phase Ib study of lenvatinib (LEN) plus nivolumab (NIV) in patients (pts) with unresectable hepatocellular carcinoma (uHCC): Study 117. J Clin Oncol. 2020. 38(4_suppl):513–513.

[73] Qin, S., S.L. Chan, S. Gu, et al., Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study. Lancet. 2023. 402(10408):1133–1146.https://doi.org/10.1016/s0140-6736(23)00961-3

[74] Kudo M, RS Finn, Ikeda M, et al. A Phase 1b Study of Lenvatinib plus Pembrolizumab in Patients with Unresectable Hepatocellular Carcinoma: Extended Analysis of Study 116. Liver Cancer (2235–1795). 2024;13(4):451-8.

[75] Ikeda, M., M.W. Sung, M. Kudo, et al., A phase 1b trial of lenvatinib (LEN) plus pembrolizumab (PEM) in patients (pts) with unresectable hepatocellular carcinoma (uHCC). J Clin Oncol. 2018. 36(15_suppl):4076–4076.

[76] Llovet JM, Kudo M, Merle P, et al. Lenvatinib plus pembrolizumab versus lenvatinib plus placebo for advanced hepatocellular carcinoma (LEAP-002): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2023;24(12):1399–1410. https://doi.org/10.1016/s1470-2045(23)00469-2.

[77] Kudo, M., Z. Ren, Y. Guo, et al., 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.https://doi.org/10.1016/s0140-6736(24)02575-3

[78] Yau, T., A. Kaseb, A.L. Cheng, et al., Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): final results of a randomised phase 3 study. Lancet Gastroenterol Hepatol. 2024. 9(4):310–322.https://doi.org/10.1016/s2468-1253(23)00454-5

[79] Geoerger, B., H.J. Kang, M. Yalon-Oren, et al., Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1–2 trial. Lancet Oncol. 2020. 21(1):121–133.https://doi.org/10.1016/s1470-2045(19)30671-0

[80] El-Khoueiry AB, K.T., Blanc JF, et al. , International, open-label phase 2 study of regorafenib plus pembrolizumab in patients with advanced hepatocellular carcinoma (HCC) previously treated with immune checkpoint inhibitors (ICI). 2024 ASCO, 2024.

[81] Abstract 4101. ASCO 2021, 2021.

[82] al, H.L.J.M.M.Z.C.Z.J.L.e. Anlotinib plus toripalimab as first-line treatment for patients with unresectable hepatocellular carcinoma: Updated results of the ALTER-H003 trial. J Clin Oncol. 2023–01–25. https://doi.org/10.1200/jco.2023.41.4_suppl.568.

[83] Rimassa L, N. Personeni C, Czauderna, et al. Systemic treatment of HCC in special populations. J Hepatol. 2021;74(4):931–43. https://doi.org/10.1016/j.jhep.2020.11.026.

[84] Abdel-Wahab, N., M. Shah, M.A. Lopez-Olivo, et al., Use of Immune Checkpoint Inhibitors in the Treatment of Patients With Cancer and Preexisting Autoimmune Disease: A Systematic Review. Ann Intern Med. 2018. 168(2):121–130.https://doi.org/10.7326/m17-2073

[85] Kobayashi, K., S. Ogasawara, A. Takahashi, et al., Evolution of Survival Impact of Molecular Target Agents in Patients with Advanced Hepatocellular Carcinoma. Liver Cancer. 2022. 11(1):48–60.https://doi.org/10.1159/000519868

[86] Sadelain, M., R. Brentjens and I. Rivière, The basic principles of chimeric antigen receptor design. Cancer Discov. 2013. 3(4):388–98.https://doi.org/10.1158/2159-8290.Cd-12-0548

[87] Donne, R. and A. Lujambio, The liver cancer immune microenvironment: Therapeutic implications for hepatocellular carcinoma. Hepatology. 2023. 77(5):1773–1796.https://doi.org/10.1002/hep.32740

[88] Gao, H., K. Li, H. Tu, et al., Development of T cells redirected to glypican-3 for the treatment of hepatocellular carcinoma. Clin Cancer Res. 2014. 20(24):6418–28.https://doi.org/10.1158/1078-0432.Ccr-14-1170

[89] Zhang, Q., Q. Fu, W. Cao, et al., Phase I study of C-CAR031, a GPC3-specific TGFβRIIDN armored autologous CAR-T, in patients with advanced hepatocellular carcinoma (HCC). J Clin Oncol. 2024. 42(16_suppl):4019–4019.

[90] Guo, J. and Q. Tang, Recent updates on chimeric antigen receptor T cell therapy for hepatocellular carcinoma. Cancer Gene Ther. 2021. 28(10–11):1075–1087.https://doi.org/10.1038/s41417-020-00259-4

[91] Liu, H., Y. Xu, J. Xiang, et al., Targeting Alpha-Fetoprotein (AFP)-MHC Complex with CAR T-Cell Therapy for Liver Cancer. Clin Cancer Res. 2017. 23(2):478–488.https://doi.org/10.1158/1078-0432.Ccr-16-1203

[92] Liu, Z., H. Wang, H. Liu, et al., Targeting NKG2D/NKG2DL axis in multiple myeloma therapy. Cytokine Growth Factor Rev. 2024. 76:1–11.https://doi.org/10.1016/j.cytogfr.2024.02.001

[93] Cadoux, M., S. Caruso, S. Pham, et al., Expression of NKG2D ligands is downregulated by β-catenin signalling and associates with HCC aggressiveness. J Hepatol. 2021. 74(6):1386–1397.https://doi.org/10.1016/j.jhep.2021.01.017

[94] Lin, M.J., J. Svensson-Arvelund, G.S. Lubitz, et al., Cancer vaccines: the next immunotherapy frontier. Nat Cancer. 2022. 3(8):911–926.https://doi.org/10.1038/s43018-022-00418-6

[95] Zhao, G., Y. Jiang, P. Ma, et al., The clinical landscape of therapeutic cancer vaccines: the next breakthrough in cancer immunotherapy? Eur J Cancer. 2023. 181:38–41.https://doi.org/10.1016/j.ejca.2022.12.007

[96] Schiller, J.T., D.R. Lowy, I.H. Frazer, et al., Cancer vaccines. Cancer Cell. 2022. 40(6):559–564.https://doi.org/10.1016/j.ccell.2022.05.015

[97] Wan, X., K. Wisskirchen, T. Jin, et al., Genetically-modified, redirected T cells target hepatitis B surface antigen-positive hepatocytes and hepatocellular carcinoma lesions in a clinical setting. Clin Mol Hepatol. 2024. 30(4):735–755.https://doi.org/10.3350/cmh.2024.0058

[98] Zheng, X., Y. Wu, J. Bi, et al., The use of supercytokines, immunocytokines, engager cytokines, and other synthetic cytokines in immunotherapy. Cell Mol Immunol. 2022. 19(2):192–209.https://doi.org/10.1038/s41423-021-00786-6

[99] Yu, S.J., Immunotherapy for hepatocellular carcinoma: Recent advances and future targets. Pharmacol Ther. 2023. 244:108387.https://doi.org/10.1016/j.pharmthera.2023.108387

[100] Kaufman, H.L., F.J. Kohlhapp and A. Zloza, Oncolytic viruses: a new class of immunotherapy drugs. Nat Rev Drug Discov. 2015. 14(9):642–62.https://doi.org/10.1038/nrd4663

[101] Tian, Y., D. Xie and L. Yang, Engineering strategies to enhance oncolytic viruses in cancer immunotherapy. Signal Transduct Target Ther. 2022. 7(1):117.https://doi.org/10.1038/s41392-022-00951-x

[102] Hemminki O, Santos JMD, Hemminki A. Oncolytic viruses for cancer immunotherapy. J Hematol Oncol. 2020;13(1):84.

[103] Andtbacka, R.H., H.L. Kaufman, F. Collichio, et al., Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma. J Clin Oncol. 2015. 33(25):2780–8.https://doi.org/10.1200/jco.2014.58.3377

[104] Todo T, Ito H, Ino Y, et al. Intratumoral oncolytic herpes virus G47∆ for residual or recurrent glioblastoma: a phase 2 trial. Nat Med. 2022;28(8):1630–9. https://doi.org/10.1038/s41591-022-01897-x.

[105] Park, B.H., T. Hwang, T.C. Liu, et al., Use of a targeted oncolytic poxvirus, JX-594, in patients with refractory primary or metastatic liver cancer: a phase I trial. Lancet Oncol. 2008. 9(6):533–42.https://doi.org/10.1016/s1470-2045(08)70107-4

[106] Breitbach, C.J., R. Arulanandam, N. De Silva, et al., Oncolytic vaccinia virus disrupts tumor-associated vasculature in humans. Cancer Res. 2013. 73(4):1265–75.https://doi.org/10.1158/0008-5472.Can-12-2687

[107] Greten, T.F., A. Villanueva, F. Korangy, et al., Biomarkers for immunotherapy of hepatocellular carcinoma. Nat Rev Clin Oncol. 2023. 20(11):780–798.https://doi.org/10.1038/s41571-023-00816-4

[108] Hanna, N.H., A.G. Robinson, S. Temin, et al., Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO and OH (CCO) Joint Guideline Update. J Clin Oncol. 2021. 39(9):1040–1091.https://doi.org/10.1200/jco.20.03570

[109] Yau, T., Y.K. Kang, T.Y. Kim, et al., Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib: The CheckMate 040 Randomized Clinical Trial. JAMA Oncol. 2020. 6(11):e204564.https://doi.org/10.1001/jamaoncol.2020.4564

[110] Snyder, A., V. Makarov, T. Merghoub, et al., Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014. 371(23):2189–2199.https://doi.org/10.1056/NEJMoa1406498

[111] Zhu, A.X., A.R. Abbas, M.R. de Galarreta, et al., Molecular correlates of clinical response and resistance to atezolizumab in combination with bevacizumab in advanced hepatocellular carcinoma. Nat Med. 2022. 28(8):1599–1611.https://doi.org/10.1038/s41591-022-01868-2

[112] Hause, R.J., C.C. Pritchard, J. Shendure, et al., Classification and characterization of microsatellite instability across 18 cancer types. Nat Med. 2016. 22(11):1342–1350.https://doi.org/10.1038/nm.4191

[113] Eso, Y., T. Shimizu, H. Takeda, et al., Microsatellite instability and immune checkpoint inhibitors: toward precision medicine against gastrointestinal and hepatobiliary cancers. J Gastroenterol. 2020. 55(1):15–26.https://doi.org/10.1007/s00535-019-01620-7

[114] Kawaoka, T., Y. Ando, M. Yamauchi, et al., Incidence of microsatellite instability-high hepatocellular carcinoma among Japanese patients and response to pembrolizumab. Hepatol Res. 2020. 50(7):885–888.https://doi.org/10.1111/hepr.13496

[115] Ngiow, S.F., A. Young, N. Jacquelot, et al., A Threshold Level of Intratumor CD8+ T-cell PD1 Expression Dictates Therapeutic Response to Anti-PD1. Cancer Res. 2015. 75(18):3800–11.https://doi.org/10.1158/0008-5472.Can-15-1082

[116] Zhao, C., X. Pang, Z. Yang, et al., Nanomaterials targeting tumor associated macrophages for cancer immunotherapy. J Control Release. 2022. 341:272–284.https://doi.org/10.1016/j.jconrel.2021.11.028

[117] Yeung, O.W., C.M. Lo, C.C. Ling, et al., Alternatively activated (M2) macrophages promote tumour growth and invasiveness in hepatocellular carcinoma. J Hepatol. 2015. 62(3):607–16.https://doi.org/10.1016/j.jhep.2014.10.029

[118] Riaz, N., J.J. Havel, V. Makarov, et al., Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab. Cell. 2017. 171(4):934–949.e16.https://doi.org/10.1016/j.cell.2017.09.028

[119] He, M., Y. Liu, S. Chen, et al., Serum amyloid A promotes glycolysis of neutrophils during PD-1 blockade resistance in hepatocellular carcinoma. Nat Commun. 2024. 15(1):1754.https://doi.org/10.1038/s41467-024-46118-w

[120] Wang, S., R. Wang, N. Xu, et al., SULT2B1-CS-DOCK2 axis regulates effector T-cell exhaustion in HCC microenvironment. Hepatol. 2023. 78(4):1064–1078.https://doi.org/10.1097/hep.0000000000000025

[121] Baxi, S., A. Yang, R.L. Gennarelli, et al., Immune-related adverse events for anti-PD-1 and anti-PD-L1 drugs: systematic review and meta-analysis. Bmj. 2018. 360:k793.https://doi.org/10.1136/bmj.k793

[122] Ng, K.Y.Y., S.H. Tan, J.J.E. Tan, et al., Impact of Immune-Related Adverse Events on Efficacy of Immune Checkpoint Inhibitors in Patients with Advanced Hepatocellular Carcinoma. Liver Cancer. 2022. 11(1):9–21.https://doi.org/10.1159/000518619

[123] Duffy, A.G., S.V. Ulahannan, O. Makorova-Rusher, et al., Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma. J Hepatol. 2017. 66(3):545–551.https://doi.org/10.1016/j.jhep.2016.10.029

[124] Sangro, B., M. Kudo, J.P. Erinjeri, et al., Durvalumab with or without bevacizumab with transarterial chemoembolisation in hepatocellular carcinoma (EMERALD-1): a multiregional, randomised, double-blind, placebo-controlled, phase 3 study. Lancet. 2025. 405(10474):216–232.https://doi.org/10.1016/s0140-6736(24)02551-0

[125] He, M.K., R.B. Liang, Y. Zhao, et al., Lenvatinib, toripalimab, plus hepatic arterial infusion chemotherapy versus lenvatinib alone for advanced hepatocellular carcinoma. Ther Adv Med Oncol. 2021. 13:17588359211002720.https://doi.org/10.1177/17588359211002720

[126] Zhong, B.Y., W. Fan, J.J. Guan, et al., Combination locoregional and systemic therapies in hepatocellular carcinoma. Lancet Gastroenterol Hepatol. 2025. 10(4):369–386.https://doi.org/10.1016/s2468-1253(24)00247-4

[127] Lai, Z., M. He, X. Bu, et al., Lenvatinib, toripalimab plus hepatic arterial infusion chemotherapy in patients with high-risk advanced hepatocellular carcinoma: A biomolecular exploratory, phase II trial. Eur J Cancer. 2022. 174:68–77.https://doi.org/10.1016/j.ejca.2022.07.005

[128] Ma, K., L. Wang, W. Li, et al., Turning cold into hot: emerging strategies to fire up the tumor microenvironment. Trends Cancer, 2025. 11(2):117–134.https://doi.org/10.1016/j.trecan.2024.11.011

Funding

National Natural Science Foundation of China(882073217)

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