Interactions between tumor microenvironment and resistance to transarterial and systemic treatments for HCC

Abstract

Hepatocellular carcinoma (HCC) is a malignant tumor originating from hepatocytes, often developing against a backdrop of chronic inflammation and liver fibrosis. The primary risk factor for HCC is cirrhosis, and early detection is crucial for improving outcomes. Despite advances in treatment, the prognosis remains poor, with a 5-year survival rate of approximately 15%-38%. Growing evidence highlights the critical role of the tumor microenvironment (TME) in modulating tumor initiation, growth, progression, and, in some cases, suppression. The TME is a complex ecosystem composed of immune cells, cancer-associated fibroblasts, extracellular matrix components, and other factors such as growth factors and cytokines. By shaping tumor cell behavior, the TME facilitates immune evasion and contributes to resistance to treatment. Tumor-associated immune cells, including regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages, contribute to immune suppression and progression. On the other hand, immune activation via immune checkpoint inhibition has shown promise in improving outcomes, especially when combined with other treatments such as transarterial chemoembolization (TACE), selective internal radiation therapy (SIRT), and systemic therapies. Studies have demonstrated the potential of targeting the TME to enhance treatment efficacy, with immune modulation emerging as a key therapeutic strategy. This review explores the complex interactions within the TME in HCC, highlighting its role in therapy resistance and immune evasion. It also discusses current therapeutic approaches to target the TME to improve clinical outcomes in HCC patients.

Keywords

Hepatocellular carcinoma / extracellular matrix / transarterial chemoembolization / selective internal radiation therapy / systemic therapy / drug resistance / immune evasion / immune checkpoint inhibitors

References

[1] Rumgay H,Ferlay J.Global burden of primary liver cancer in 2020 and predictions to 2040.J Hepatol2022;77:1598-606 PMCID:PMC9670241

[2] Kulik L.Epidemiology and management of hepatocellular carcinoma.Gastroenterology2019;156:477-91.e1 PMCID:PMC6340716

[3] Sung H,Siegel RL.Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin2021;71:209-49

[4] Llovet JM,Villanueva A.Hepatocellular carcinoma.Nat Rev Dis Primers2021;7:6

[5] Singal AG,Nahon P.Epidemiology and surveillance for hepatocellular carcinoma: new trends.J Hepatol2020;72:250-61 PMCID:PMC6986771

[6] Villanueva A.Hepatocellular carcinoma.N Engl J Med2019;380:1450-62

[7] European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of hepatocellular carcinoma.J Hepatol2018;69:182-236

[8] Xu L,Spolverato G,Pawlik TM.Racial disparities in treatment and survival of patients with hepatocellular carcinoma in the United States.Hepatobiliary Surg Nutr2016;5:43-52 PMCID:PMC4739939

[9] Altekruse SF,Cucinelli JE.Changing hepatocellular carcinoma incidence and liver cancer mortality rates in the United States.Am J Gastroenterol2014;109:542-53 PMCID:PMC4148914

[10] Koza A,Fotiadis N.The role of ablative techniques in the management of hepatocellular carcinoma: indications and outcomes.Biomedicines2023;11:1062 PMCID:PMC10135821

[11] Reig M,Rimola J.BCLC strategy for prognosis prediction and treatment recommendation: the 2022 update.J Hepatol2022;76:681-93 PMCID:PMC8866082

[12] Llovet JM,Kulik L.Locoregional therapies in the era of molecular and immune treatments for hepatocellular carcinoma.Nat Rev Gastroenterol Hepatol2021;18:293-313

[13] Llovet JM,Heikenwalder M.Immunotherapies for hepatocellular carcinoma.Nat Rev Clin Oncol2022;19:151-72

[14] Liu Y,Ma K.Identification of a tumour immune barrier in the HCC microenvironment that determines the efficacy of immunotherapy.J Hepatol2023;78:770-82

[15] Galasso L,Maccauro V.Hepatocellular carcinoma and the multifaceted relationship with its microenvironment: attacking the hepatocellular carcinoma defensive fortress.Cancers2024;16:1837 PMCID:PMC11119751

[16] Ladd AD,Sahin I.Mechanisms of drug resistance in HCC.Hepatology2024;79:926-40

[17] Hinshaw DC.The tumor microenvironment innately modulates cancer progression.Cancer Res2019;79:4557-66 PMCID:PMC6744958

[18] Chen C,Ding Y.Tumor microenvironment-mediated immune evasion in hepatocellular carcinoma.Front Immunol2023;14:1133308 PMCID:PMC9950271

[19] Robinson MW,O’Farrelly C.Liver immunology and its role in inflammation and homeostasis.Cell Mol Immunol2016;13:267-76 PMCID:PMC4856809

[20] Hanahan D.Accessories to the crime: functions of cells recruited to the tumor microenvironment.Cancer Cell2012;21:309-22

[21] Volponi C,Bonavita E.The tumor microenvironment of hepatocellular carcinoma: untying an intricate immunological network.Cancers2022;14:6151 PMCID:PMC9776867

[22] Williams MA,Bevan MJ.Interleukin-2 signals during priming are required for secondary expansion of CD8+ memory T cells.Nature2006;441:890-3 PMCID:PMC2776073

[23] Hao X,Zhang Y.Targeting immune cells in the tumor microenvironment of HCC: new opportunities and challenges.Front Cell Dev Biol2021;9:775462 PMCID:PMC8633569

[24] Wang H,Wu X.Cancer-associated fibroblasts contributed to hepatocellular carcinoma recurrence and metastasis via CD36-mediated fatty-acid metabolic reprogramming.Exp Cell Res2024;435:113947

[25] Su L,Yan Y.Extracellular vesicles in hepatocellular carcinoma: unraveling immunological mechanisms for enhanced diagnosis and overcoming drug resistance.Front Immunol2024;15:1485628 PMCID:PMC11550962

[26] Gupta T.Hepatocellular carcinoma immune microenvironment and check point inhibitors-current status.World J Hepatol2024;16:353-65 PMCID:PMC10989304

[27] Mignini I,Galasso L.From the colon to the liver: how gut microbiota may influence colorectal cancer metastatic potential.J Clin Med2024;13:420 PMCID:PMC10815973

[28] Nishida N.Immunological microenvironment of hepatocellular carcinoma and its clinical implication.Oncology2017;92 Suppl 1:40-9

[29] Bai Y,Cheng C.Immunosuppressive landscape in hepatocellular carcinoma revealed by single-cell sequencing.Front Immunol2022;13:950536 PMCID:PMC9365996

[30] Xia C,Zhu Y.Identification of DLAT as a potential therapeutic target via a novel cuproptosis-related gene signature for the prediction of liver cancer prognosis.J Gastrointest Oncol2024;15:2230-51 PMCID:PMC11565118

[31] Cariani E.Immune landscape of hepatocellular carcinoma microenvironment: implications for prognosis and therapeutic applications.Liver Int2019;39:1608-21

[32] Barry KC,Broz ML.A natural killer-dendritic cell axis defines checkpoint therapy-responsive tumor microenvironments.Nat Med2018;24:1178-91 PMCID:PMC6475503

[33] Böttcher JP,Chakravarty P.NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control.Cell2018;172:1022-37.e14 PMCID:PMC5847168

[34] Chen DS.Oncology meets immunology: the cancer-immunity cycle.Immunity2013;39:1-10

[35] Zheng L,Si W.Pan-cancer single-cell landscape of tumor-infiltrating T cells.Science2021;374:abe6474

[36] Ma L,Zhao Y.Tumor cell biodiversity drives microenvironmental reprogramming in liver cancer.Cancer Cell2019;36:418-30.e6 PMCID:PMC6801104

[37] Iñarrairaegui M,Sangro B.Immunotherapy of hepatocellular carcinoma: facts and hopes.Clin Cancer Res2018;24:1518-24

[38] Peng W,Liu C.Loss of PTEN promotes resistance to T cell-mediated immunotherapy.Cancer Discov2016;6:202-16 PMCID:PMC4744499

[39] Lu C,Zhang B.Current perspectives on the immunosuppressive tumor microenvironment in hepatocellular carcinoma: challenges and opportunities.Mol Cancer2019;18:130 PMCID:PMC6714090

[40] Jaillon S,Di Mitri D,Bonecchi R.Neutrophil diversity and plasticity in tumour progression and therapy.Nat Rev Cancer2020;20:485-503

[41] Zhou SL,Hu ZQ.Tumor-associated neutrophils recruit macrophages and T-regulatory cells to promote progression of hepatocellular carcinoma and resistance to sorafenib.Gastroenterology2016;150:1646-58.e17

[42] Yang LY,Lu L.Increased neutrophil extracellular traps promote metastasis potential of hepatocellular carcinoma via provoking tumorous inflammatory response.J Hematol Oncol2020;13:3 PMCID:PMC6945602

[43] Sun R,Liu H.Tumor-associated neutrophils suppress antitumor immunity of NK cells through the PD-L1/PD-1 axis.Transl Oncol2020;13:100825 PMCID:PMC7372151

[44] Guan X,Zhu H.The crosstalk between cancer cells and neutrophils enhances hepatocellular carcinoma metastasis via neutrophil extracellular traps-associated cathepsin G component: a potential therapeutic target.J Hepatocell Carcinoma2021;8:451-65 PMCID:PMC8144903

[45] Li XF,Ouyang FZ.Increased autophagy sustains the survival and pro-tumourigenic effects of neutrophils in human hepatocellular carcinoma.J Hepatol2015;62:131-9

[46] Thommen DS,Herzig P.A transcriptionally and functionally distinct PD-1⁺ CD8⁺ T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade.Nat Med2018;24:994-1004 PMCID:PMC6110381

[47] Kunitani H,Murata H,Watanabe A.Phenotypic analysis of circulating and intrahepatic dendritic cell subsets in patients with chronic liver diseases.J Hepatol2002;36:734-41

[48] Thaiss CA,Franken L,Kurts C.Chemokines: a new dendritic cell signal for T cell activation.Front Immunol2011;2:31 PMCID:PMC3342358

[49] Chen C,Zhang YT.Effect of dendritic cell-based immunotherapy on hepatocellular carcinoma: a systematic review and meta-analysis.Cytotherapy2018;20:975-89

[50] Huang Y,Zhou J,Qian X.The role of tumor associated macrophages in hepatocellular carcinoma.J Cancer2021;12:1284-94 PMCID:PMC7847664

[51] Dong P,Liu L.CD86⁺/CD206⁺, diametrically polarized tumor-associated macrophages, predict hepatocellular carcinoma patient prognosis.Int J Mol Sci2016;17:320 PMCID:PMC4813183

[52] Zhu Y,Xu D.Disruption of tumour-associated macrophage trafficking by the osteopontin-induced colony-stimulating factor-1 signalling sensitises hepatocellular carcinoma to anti-PD-L1 blockade.Gut2019;68:1653-66

[53] Zhu XD,Zhuang PY.High expression of macrophage colony-stimulating factor in peritumoral liver tissue is associated with poor survival after curative resection of hepatocellular carcinoma.J Clin Oncol2008;26:2707-16

[54] Veglia F,Gabrilovich DI.Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity.Nat Rev Immunol2021;21:485-98 PMCID:PMC7849958

[55] Hoechst B,Ormandy L.Myeloid derived suppressor cells inhibit natural killer cells in patients with hepatocellular carcinoma via the NKp30 receptor.Hepatology2009;50:799-807 PMCID:PMC6357774

[56] Erez N,Olson P,Hanahan D.Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-kappaB-dependent manner.Cancer Cell2010;17:135-47

[57] Deng Y,Fu B.Hepatic carcinoma-associated fibroblasts enhance immune suppression by facilitating the generation of myeloid-derived suppressor cells.Oncogene2017;36:1090-101

[58] Zhang Q,Luo N.Landscape and dynamics of single immune cells in hepatocellular carcinoma.Cell2019;179:829-45.e20

[59] Guo X,Zheng L.Global characterization of T cells in non-small-cell lung cancer by single-cell sequencing.Nat Med2018;24:978-85

[60] Newell EW.Mass cytometry: blessed with the curse of dimensionality.Nat Immunol2016;17:890-5

[61] Giesen C,Schapiro D.Highly multiplexed imaging of tumor tissues with subcellular resolution by mass cytometry.Nat Methods2014;11:417-22

[62] Wan JCM,Garcia-Corbacho J.Liquid biopsies come of age: towards implementation of circulating tumour DNA.Nat Rev Cancer2017;17:223-38

[63] European Association for the Study of the Liver. EASL Clinical Practice Guidelines on the management of hepatocellular carcinoma.J Hepatol2025;82:315-74

[64] Forner A,Bruix J.Treatment of intermediate-stage hepatocellular carcinoma.Nat Rev Clin Oncol2014;11:525-35

[65] Ebeling Barbier C, Heindryckx F, Lennernäs H. Limitations and possibilities of transarterial chemotherapeutic treatment of hepatocellular carcinoma.Int J Mol Sci2021;22:13051 PMCID:PMC8658005

[66] Liu Z,Wang Y.Hypoxia accelerates aggressiveness of hepatocellular carcinoma cells involving oxidative stress, epithelial-mesenchymal transition and non-canonical hedgehog signaling.Cell Physiol Biochem2017;44:1856-68

[67] de Baere T, Plotkin S, Yu R, Sutter A, Wu Y, Cruise GM. An in vitro evaluation of four types of drug-eluting microspheres loaded with doxorubicin.J Vasc Interv Radiol2016;27:1425-31

[68] Kim MJ,Oh BS.Change in inflammatory cytokine profiles after transarterial chemotherapy in patients with hepatocellular carcinoma.Cytokine2013;64:516-22

[69] Padia SA.Is idarubicin the future of TACE?.Radiology2019;291:809-10

[70] Katayama K,Abe Y.Number of nodules but not size of hepatocellular carcinoma can predict refractoriness to transarterial chemoembolization and poor prognosis.J Clin Med Res2018;10:765-71 PMCID:PMC6135006

[71] Kudo M, Matsui O, Izumi N, et al; Liver Cancer Study Group of Japan. Transarterial chemoembolization failure/refractoriness: JSH-LCSGJ criteria 2014 update. Oncology. 2014;87 Suppl 1:22-31.

[72] Choi J,Shim JH.Evaluation of transarterial chemoembolization refractoriness in patients with hepatocellular carcinoma.PLoS One2020;15:e0229696 PMCID:PMC7055892

[73] Tak E,Lee J.Human carbonyl reductase 1 upregulated by hypoxia renders resistance to apoptosis in hepatocellular carcinoma cells.J Hepatol2011;54:328-39

[74] Singh P,Avula A,Rahma OE.The immune modulation effect of locoregional therapies and its potential synergy with immunotherapy in hepatocellular carcinoma.J Hepatocell Carcinoma2020;7:11-7 PMCID:PMC7022138

[75] Tampaki M,Hadziyannis E,Malagari K.Association of TIM-3 with BCLC stage, serum PD-L1 detection, and response to transarterial chemoembolization in patients with hepatocellular carcinoma.Cancers2020;12:212 PMCID:PMC7016746

[76] Jekarl DW,Kwon JH.Complex interaction networks of cytokines after transarterial chemotherapy in patients with hepatocellular carcinoma.PLoS One2019;14:e0224318 PMCID:PMC6874208

[77] Pinato DJ,Arizumi T.Dynamic changes of the inflammation-based index predict mortality following chemoembolisation for hepatocellular carcinoma: a prospective study.Aliment Pharmacol Ther2014;40:1270-81

[78] Pinato DJ,Forner A.Trans-arterial chemoembolization as a loco-regional inducer of immunogenic cell death in hepatocellular carcinoma: implications for immunotherapy.J Immunother Cancer2021;9:e003311 PMCID:PMC8487214

[79] Tan J,Liu T.TREM2⁺ macrophages suppress CD8⁺ T-cell infiltration after transarterial chemoembolisation in hepatocellular carcinoma.J Hepatol2023;79:126-40

[80] Cappelli A,Cabibbo G.Refining prognosis after trans-arterial chemo-embolization for hepatocellular carcinoma.Liver Int2016;36:729-36

[81] Kadalayil L,Pallan L.A simple prognostic scoring system for patients receiving transarterial embolisation for hepatocellular cancer.Ann Oncol2013;24:2565-70 PMCID:PMC4023407

[82] Tang Y,Xue M,Fan W.A 10-gene signature identified by machine learning for predicting the response to transarterial chemoembolization in patients with hepatocellular carcinoma.J Oncol2022;2022:3822773 PMCID:PMC8803430

[83] Fako V,Pomyen Y.Gene signature predictive of hepatocellular carcinoma patient response to transarterial chemoembolization.Int J Biol Sci2019;15:2654-63 PMCID:PMC6854367

[84] Huang M,Chen J.Regulation of COX-2 expression and epithelial-to-mesenchymal transition by hypoxia-inducible factor-1α is associated with poor prognosis in hepatocellular carcinoma patients post TACE surgery.Int J Oncol2016;48:2144-54 PMCID:PMC4809660

[85] He Q,Jin Y.Development and validation of TACE refractoriness-related diagnostic and prognostic scores and characterization of tumor microenvironment infiltration in hepatocellular carcinoma.Front Immunol2022;13:869993 PMCID:PMC9043752

[86] Wang L,Liu Z.Enhanced interactions within microenvironment accelerates dismal prognosis in HBV-related HCC after TACE.Hepatol Commun2024;8:e0548 PMCID:PMC11458170

[87] Yue Y,Wang Y.Impact of microparticle transarterial chemoembolization (mTACE) on myeloid-derived suppressor cell subtypes in hepatocellular carcinoma: clinical correlations and therapeutic implications.Immun Inflamm Dis2024;12:e70007 PMCID:PMC11367920

[88] Wang C,You R.A transcriptomic biomarker for predicting the response to TACE correlates with the tumor microenvironment and radiomics features in hepatocellular carcinoma.J Hepatocell Carcinoma2024;11:2321-37 PMCID:PMC11606151

[89] Ayaru L,Alisa A.Unmasking of alpha-fetoprotein-specific CD4⁺ T cell responses in hepatocellular carcinoma patients undergoing embolization.J Immunol2007;178:1914-22

[90] Xue J,Wang F,Niu M.Advances in locoregional therapy for hepatocellular carcinoma combined with immunotherapy and targeted therapy.J Interv Med2021;4:105-13 PMCID:PMC8562181

[91] El Fouly A,El Dorry A.In intermediate stage hepatocellular carcinoma: radioembolization with yttrium 90 or chemoembolization?.Liver Int2015;35:627-35

[92] Kallini JR,Salem R.Transarterial radioembolization with Yttrium-90 for the treatment of hepatocellular carcinoma.Adv Ther2016;33:699-714 PMCID:PMC4882351

[93] Salem R,Mulcahy MF.Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report of long-term outcomes.Gastroenterology2010;138:52-64

[94] Franzè MS,Sessa A.Prognostic factors influencing outcomes in hepatocellular carcinoma patients undergoing selective internal radiation therapy.Ann Hepatol2025;30:101539

[95] Lugade AA,Gerber SA,Frelinger JG.Radiation-induced IFN-gamma production within the tumor microenvironment influences antitumor immunity.J Immunol2008;180:3132-9

[96] Barcellos-Hoff MH,Wright EG.Radiation and the microenvironment - tumorigenesis and therapy.Nat Rev Cancer2005;5:867-75

[97] Chew V,Teo M.Inflammatory tumour microenvironment is associated with superior survival in hepatocellular carcinoma patients.J Hepatol2010;52:370-9

[98] Chew V,Pan L.Immune activation underlies a sustained clinical response to Yttrium-90 radioembolisation in hepatocellular carcinoma.Gut2019;68:335-46 PMCID:PMC6352403

[99] Bitar R,Finn R,Goldberg SN.Interventional oncology meets immuno-oncology: combination therapies for hepatocellular carcinoma.Radiology2024;313:e232875 PMCID:PMC11605110

[100] Giraud J,Blanc JF.Hepatocellular carcinoma immune landscape and the potential of immunotherapies.Front Immunol2021;12:655697 PMCID:PMC8012774

[101] Farhood B,Mortezaee K.CD8⁺ cytotoxic T lymphocytes in cancer immunotherapy: a review.J Cell Physiol2019;234:8509-21

[102] Wherry EJ.Molecular and cellular insights into T cell exhaustion.Nat Rev Immunol2015;15:486-99 PMCID:PMC4889009

[103] Chen L,Huang Z.Prognostic values of tissue-resident CD8⁺T cells in human hepatocellular carcinoma and intrahepatic cholangiocarcinoma.World J Surg Oncol2023;21:124 PMCID:PMC10077621

[104] Li Z,Qiu X.The identification and functional analysis of CD8+PD-1+CD161+ T cells in hepatocellular carcinoma.NPJ Precis Oncol2020;4:28 PMCID:PMC7599220

[105] Ye L,Tang H.CD8+CXCR5+T cells infiltrating hepatocellular carcinomas are activated and predictive of a better prognosis.Aging2019;11:8879-91 PMCID:PMC6834425

[106] Abushukair HM.Hepatocellular carcinoma and immunotherapy: beyond immune checkpoint inhibitors.World J Gastrointest Oncol2022;14:1210-2 PMCID:PMC9244992

[107] Duan Q,Zheng J.Turning cold into hot: firing up the tumor microenvironment.Trends Cancer2020;6:605-18

[108] Ailia MJ,Yoo SY.Navigating through the PD-1/PDL-1 landscape: a systematic review and meta-analysis of clinical outcomes in hepatocellular carcinoma and their influence on immunotherapy and tumor microenvironment.Int J Mol Sci2023;24:6495 PMCID:PMC10095164

[109] Kudo M.Pembrolizumab for the treatment of hepatocellular carcinoma.Liver Cancer2019;8:143-54 PMCID:PMC6547263

[110] Zhu AX, Finn RS, Edeline J, et al; KEYNOTE-224 investigators. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018;19:940-52.

[111] El-Khoueiry AB,Yau T.Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial.Lancet2017;389:2492-502 PMCID:PMC7539326

[112] Finn RS, Ryoo BY, Merle P, et al; KEYNOTE-240 investigators. 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;38:193-202.

[113] Sangro B,Finn R.LBA-3 CheckMate 459: long-term (minimum follow-up 33.6 months) survival outcomes with nivolumab versus sorafenib as first-line treatment in patients with advanced hepatocellular carcinoma.Ann Oncol2020;31:S241-2

[114] Finn RS, Qin S, Ikeda M, et al; IMbrave150 Investigators. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382:1894-905.

[115] Salem R,Sommer N.Characterization of response to atezolizumab+bevacizumab versus sorafenib for hepatocellular carcinoma: results from the IMbrave150 trial.Cancer Med2021;10:5437-47 PMCID:PMC8366100

[116] D’Alessio A,Nishida N.Preliminary evidence of safety and tolerability of atezolizumab plus bevacizumab in patients with hepatocellular carcinoma and Child-Pugh A and B cirrhosis: a real-world study.Hepatology2022;76:1000-12 PMCID:PMC9790703

[117] Sangro B,de la Mata M.A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C.J Hepatol2013;59:81-8

[118] Abou-alfa GK,Kudo M.Phase 3 randomized, open-label, multicenter study of tremelimumab (T) and durvalumab (D) as first-line therapy in patients (pts) with unresectable hepatocellular carcinoma (uHCC): HIMALAYA.J Clin Oncol2022;40:379

[119] Yau T,Kim TY.Efficacy and safety of nivolumab plus ipilimumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib: the CheckMate 040 randomized clinical trial.JAMA Oncol2020;6:e204564 PMCID:PMC7530824

[120] Zuo D,Wang K.A novel LAG3 neutralizing antibody improves cancer immunotherapy by dual inhibition of MHC-II and FGL1 ligand binding.Biomed Pharmacother2024;175:116782

[121] Yang C,Zhao Y.Fibrinogen-like protein 1 promotes liver-resident memory T-cell exhaustion in hepatocellular carcinoma.Front Immunol2023;14:1112672 PMCID:PMC10040674

[122] Hua N,Yang C.The correlation of fibrinogen-like protein-1 expression with the progression and prognosis of hepatocellular carcinoma.Mol Biol Rep2022;49:7911-9 PMCID:PMC9304048

[123] 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

[124] Morita M,Aoki T.Role of β-catenin activation in the tumor immune microenvironment and immunotherapy of hepatocellular carcinoma.Cancers2023;15:2311 PMCID:PMC10136695

[125] Harding JJ,Armenia J.Prospective genotyping of hepatocellular carcinoma: clinical implications of next-generation sequencing for matching patients to targeted and immune therapies.Clin Cancer Res2019;25:2116-26 PMCID:PMC6689131

[126] Morita M,Sakai K.Immunological microenvironment predicts the survival of the patients with hepatocellular carcinoma treated with anti-PD-1 antibody.Liver Cancer2021;10:380-93 PMCID:PMC8339510

[127] Zhu AX,de Galarreta MR.Molecular correlates of clinical response and resistance to atezolizumab in combination with bevacizumab in advanced hepatocellular carcinoma.Nat Med2022;28:1599-611

[128] Zhang C,Yin C,Liu P.STAT3 orchestrates immune dynamics in hepatocellular carcinoma: a pivotal nexus in tumor progression.Crit Rev Oncol Hematol2025;207:104620

[129] Wang Y,Liu K.The mechanism of Xihuang pills’ intervention in the tumour immune microenvironment for the treatment of liver cancer based on the STAT3-PDL1 pathway.J Ethnopharmacol2024;331:118278

[130] Blagih J,Vousden KH.p53, cancer and the immune response.J Cell Sci2020;133:jcs237453

[131] Wang J,Datar I.Fibrinogen-like protein 1 is a major immune inhibitory ligand of LAG-3.Cell2019;176:334-47.e12 PMCID:PMC6365968

[132] Yu R,Chen D.Type I interferon-mediated tumor immunity and its role in immunotherapy.Cell Mol Life Sci2022;79:191 PMCID:PMC8924142

[133] Fu Y,Sun L.Exploring the role of the immune microenvironment in hepatocellular carcinoma: implications for immunotherapy and drug resistance.Elife2024;13:e95009 PMCID:PMC11326777

[134] Kuang DM,Wu Y.Peritumoral neutrophils link inflammatory response to disease progression by fostering angiogenesis in hepatocellular carcinoma.J Hepatol2011;54:948-55

[135] Costa A,Scholer-Dahirel A.Fibroblast heterogeneity and immunosuppressive environment in human breast cancer.Cancer Cell2018;33:463-79.e10

[136] Mariathasan S,Nickles D.TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells.Nature2018;554:544-8 PMCID:PMC6028240

[137] Gudd CLC,Triantafyllou E.Activation and transcriptional profile of monocytes and CD8⁺ T cells are altered in checkpoint inhibitor-related hepatitis.J Hepatol2021;75:177-89

[138] Pinato DJ,Wang Y.Impact of corticosteroid therapy on the outcomes of hepatocellular carcinoma treated with immune checkpoint inhibitor therapy.J Immunother Cancer2020;8:e000726 PMCID:PMC7542664

[139] Kelley RK,Harris W.Safety, efficacy, and pharmacodynamics of tremelimumab plus durvalumab for patients with unresectable hepatocellular carcinoma: randomized expansion of a phase I/II study.J Clin Oncol2021;39:2991-3001 PMCID:PMC8445563

[140] Cao F,Zhang G,Zheng J.Improved clinical outcomes in advanced hepatocellular carcinoma treated with transarterial chemoembolization plus atezolizumab and bevacizumab: a bicentric retrospective study.BMC Cancer2023;23:873 PMCID:PMC10506240

[141] Cui TM,Wang JB.Adverse effects of immune-checkpoint inhibitors in hepatocellular carcinoma.Onco Targets Ther2020;13:11725-40 PMCID:PMC7678689

[142] Cheu JW.The immune microenvironment of steatotic hepatocellular carcinoma: current findings and future prospects.Hepatol Commun2024;8:e0516 PMCID:PMC11371312