Sophisticated roles of tumor microenvironment in resistance to immune checkpoint blockade therapy in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) remains a serious threat to global health, with rising incidence and mortality rates. Therapeutic options for advanced HCC are quite limited, and the overall prognosis remains poor. Recent advancements in immunotherapy, particularly immune-checkpoint blockade (ICB) targeting anti-PD1/PD-L1 and anti-CTLA4, have facilitated a paradigm shift in cancer treatment, demonstrating substantial survival benefits across various cancer types, including HCC. However, only a subset of HCC patients exhibit a favorable response to ICB therapy, and its efficacy is often hindered by the development of resistance. There are many studies to explore the underlying mechanisms of ICB response. In this review, we compiled the latest progression in immunotherapies for HCC and systematically summarized the sophisticated mechanisms by which components of the tumor microenvironment (TME) regulate resistance to ICB therapy. Additionally, we also outlined some scientific rationale strategies to boost antitumor immunity and enhance the efficacy of ICB in HCC. These insights may serve as a roadmap for future research and help improve outcomes for HCC patients.

Keywords

Hepatocellular carcinoma / immunotherapy / immune-checkpoint blockade / tumor microenvironment

References

[1] 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

[2] Kim YS.Hepatocellular carcinoma.N Engl J Med2019;381:e2

[3] Li X,Pfister D,Zender L.The immunological and metabolic landscape in primary and metastatic liver cancer.Nat Rev Cancer2021;21:541-57

[4] Yang C,Zhang L.Evolving therapeutic landscape of advanced hepatocellular carcinoma.Nat Rev Gastroenterol Hepatol2023;20:203-22

[5] Shi J,Tu X.Single-cell immune signature for detecting early-stage HCC and early assessing anti-PD-1 immunotherapy efficacy.J Immunother Cancer2022;10:e003133 PMCID:PMC8804705

[6] 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.

[7] 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

[8] Whiteside TL,Rodriguez-Ruiz ME,Melero I.Emerging opportunities and challenges in cancer immunotherapy.Clin Cancer Res2016;22:1845-55 PMCID:PMC4943317

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

[10] Oura K,Tani J.Tumor immune microenvironment and immunosuppressive therapy in hepatocellular carcinoma: a review.Int J Mol Sci2021;22:5801 PMCID:PMC8198390

[11] Heymann F.Immunology in the liver - from homeostasis to disease.Nat Rev Gastroenterol Hepatol2016;13:88-110

[12] Fu T,Wu SY.Spatial architecture of the immune microenvironment orchestrates tumor immunity and therapeutic response.J Hematol Oncol2021;14:98 PMCID:PMC8234625

[13] Wu Y,Wang X,Gao Q.Spatial omics: navigating to the golden era of cancer research.Clin Transl Med2022;12:e696 PMCID:PMC8764875

[14] Li XY,Zhang L,Wu J.Understanding initiation and progression of hepatocellular carcinoma through single cell sequencing.Biochim Biophys Acta Rev Cancer2022;1877:188720

[15] Yu L,Shi Y.Characterization of cancer-related fibroblasts (CAF) in hepatocellular carcinoma and construction of CAF-based risk signature based on single-cell RNA-seq and bulk RNA-seq data.Front Immunol2022;13:1009789 PMCID:PMC9537943

[16] Woller N,Wirth T.Prospects and challenges for T cell-based therapies of HCC.Cells2021;10:1651 PMCID:PMC8304292

[17] Mohr R,Özdirik B.Lessons from immune checkpoint inhibitor trials in hepatocellular carcinoma.Front Immunol2021;12:652172 PMCID:PMC8042255

[18] Dong S,Han F,Wang Y.Emerging role of natural products in cancer immunotherapy.Acta Pharm Sin B2022;12:1163-85 PMCID:PMC9069318

[19] Murai H,Maesaka K.Multiomics identifies the link between intratumor steatosis and the exhausted tumor immune microenvironment in hepatocellular carcinoma.Hepatology2023;77:77-91 PMCID:PMC9970024

[20] Chen XQ,Xu D.Comprehensive analysis of KLF2 as a prognostic biomarker associated with fibrosis and immune infiltration in advanced hepatocellular carcinoma.BMC Bioinformatics2023;24:270 PMCID:PMC10308631

[21] Llovet JM,Sia D.Molecular therapies and precision medicine for hepatocellular carcinoma.Nat Rev Clin Oncol2018;15:599-616

[22] Liu Y,Wang X.Lipophagy-related gene RAB7A is involved in immune regulation and malignant progression in hepatocellular carcinoma.Comput Biol Med2023;158:106862

[23] 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

[24] Wang H,Liu Z.POSTN⁺ cancer-associated fibroblasts determine the efficacy of immunotherapy in hepatocellular carcinoma.J Immunother Cancer2024;12:e008721 PMCID:PMC11284881

[25] Li Z,Gupta S.Presence of onco-fetal neighborhoods in hepatocellular carcinoma is associated with relapse and response to immunotherapy.Nat Cancer2024;5:167-86

[26] Long F,Zhao F.DAB2⁺ macrophages support FAP⁺ fibroblasts in shaping tumor barrier and inducing poor clinical outcomes in liver cancer.Theranostics2024;14:4822-43 PMCID:PMC11373629

[27] Zhu GQ,Huang R.CD36⁺ cancer-associated fibroblasts provide immunosuppressive microenvironment for hepatocellular carcinoma via secretion of macrophage migration inhibitory factor.Cell Discov2023;9:25 PMCID:PMC9988869

[28] Gan L,Lu Y.Endosialin-positive CAFs promote hepatocellular carcinoma progression by suppressing CD8⁺ T cell infiltration.J Immunother Cancer2024;12:e009111 PMCID:PMC11535718

[29] Xu G,Yao Y.Listeria-based hepatocellular carcinoma vaccine facilitates anti-PD-1 therapy by regulating macrophage polarization.Oncogene2020;39:1429-44

[30] Wang L,Zhao JL.Targeted delivery of miR-99b reprograms tumor-associated macrophage phenotype leading to tumor regression.J Immunother Cancer2020;8:e000517 PMCID:PMC7511616

[31] Wei CY,Zhang PF.PKCα/ZFP64/CSF1 axis resets the tumor microenvironment and fuels anti-PD1 resistance in hepatocellular carcinoma.J Hepatol2022;77:163-76

[32] Chen J,Sun M.TGF-β1-induced SOX18 elevation promotes hepatocellular carcinoma progression and metastasis through transcriptionally upregulating PD-L1 and CXCL12.Gastroenterology2024;167:264-80

[33] Liu C,Xia W.Targeting ALK averts ribonuclease 1-induced immunosuppression and enhances antitumor immunity in hepatocellular carcinoma.Nat Commun2024;15:1009 PMCID:PMC10837126

[34] Wang J,Ma X.Blockage of CacyBP inhibits macrophage recruitment and improves anti-PD-1 therapy in hepatocellular carcinoma.J Exp Clin Cancer Res2023;42:303 PMCID:PMC10652496

[35] Xiang X,Zhang H.Blocking CX3CR1+ tumor-associated macrophages enhances the efficacy of anti-PD1 therapy in hepatocellular carcinoma.Cancer Immunol Res2024;12:1603-20

[36] Ning J,Shen H.Macrophage-coated tumor cluster aggravates hepatoma invasion and immunotherapy resistance via generating local immune deprivation.Cell Rep Med2024;5:101505 PMCID:PMC11148514

[37] Hao X,Liu H.Inhibition of APOC1 promotes the transformation of M2 into M1 macrophages via the ferroptosis pathway and enhances anti-PD1 immunotherapy in hepatocellular carcinoma based on single-cell RNA sequencing.Redox Biol2022;56:102463 PMCID:PMC9482117

[38] Chen J,Liu L.GOLM1 exacerbates CD8⁺ T cell suppression in hepatocellular carcinoma by promoting exosomal PD-L1 transport into tumor-associated macrophages.Signal Transduct Target Ther2021;6:397 PMCID:PMC8602261

[39] Wang X,Chen Y.Mechanism of M2 type macrophage-derived extracellular vesicles regulating PD-L1 expression via the MISP/IQGAP1 axis in hepatocellular carcinoma immunotherapy resistance.Int Immunopharmacol2023;124:110848

[40] Deng J.Overcoming the resistance of hepatocellular carcinoma to PD-1/PD-L1 inhibitor and the resultant immunosuppression by CD38 siRNA-loaded extracellular vesicles.Oncoimmunology2023;12:2152635 PMCID:PMC9809939

[41] Li Y,Xu L.Single cell analyses reveal the PD-1 blockade response-related immune features in hepatocellular carcinoma.Theranostics2024;14:3526-47 PMCID:PMC11209711

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

[43] Wu Q,Yin S.Blocking triggering receptor expressed on myeloid cells-1-positive tumor-associated macrophages induced by hypoxia reverses immunosuppression and anti-programmed cell death ligand 1 resistance in liver cancer.Hepatology2019;70:198-214 PMCID:PMC6618281

[44] Xiao N,Li K.Blocking siglec-10^hi tumor-associated macrophages improves anti-tumor immunity and enhances immunotherapy for hepatocellular carcinoma.Exp Hematol Oncol2021;10:36 PMCID:PMC8191104

[45] Li A,Yang Y.Single-cell RNA sequencing highlights the role of PVR/PVRL2 in the immunosuppressive tumour microenvironment in hepatocellular carcinoma.Front Immunol2023;14:1164448 PMCID:PMC10293927

[46] Ruf B,Babaei S.Tumor-associated macrophages trigger MAIT cell dysfunction at the HCC invasive margin.Cell2023;186:3686-705.e32 PMCID:PMC10461130

[47] Zhang F,Cai J.Activation of NOD1 on tumor-associated macrophages augments CD8⁺ T cell-mediated antitumor immunity in hepatocellular carcinoma.Sci Adv2024;10:eadp8266 PMCID:PMC11446285

[48] Sun G,Zhao J.Macrophage GSK3β-deficiency inhibits the progression of hepatocellular carcinoma and enhances the sensitivity of anti-PD1 immunotherapy.J Immunother Cancer2022;10:e005655 PMCID:PMC9772694

[49] Wu Y,Yang X.Neutrophil profiling illuminates anti-tumor antigen-presenting potency.Cell2024;187:1422-39.e24

[50] Wang Y,Zhao B.Remodeling tumor-associated neutrophils to enhance dendritic cell-based HCC neoantigen nano-vaccine efficiency.Adv Sci2022;9:e2105631 PMCID:PMC9009112

[51] Meng Y,Nie P.Immunosuppressive CD10⁺ALPL⁺ neutrophils promote resistance to anti-PD-1 therapy in HCC by mediating irreversible exhaustion of T cells.J Hepatol2023;79:1435-49

[52] Xie P,Zhang B.CRKL dictates anti-PD-1 resistance by mediating tumor-associated neutrophil infiltration in hepatocellular carcinoma.J Hepatol2024;81:93-107

[53] Yu Y,Dong B.Neutrophil extracellular traps promote immune escape in hepatocellular carcinoma by up-regulating CD73 through Notch2.Cancer Lett2024;598:217098

[54] Zheng X,Shen X.Targeting Gsk3a reverses immune evasion to enhance immunotherapy in hepatocellular carcinoma.J Immunother Cancer2024;12:e009642 PMCID:PMC11340705

[55] Leslie J,Jamieson T.CXCR2 inhibition enables NASH-HCC immunotherapy.Gut2022;71:2093-106 PMCID:PMC9484388

[56] Gao Y,Fu J.Intratumoral stem-like CCR4+ regulatory T cells orchestrate the immunosuppressive microenvironment in HCC associated with hepatitis B.J Hepatol2022;76:148-59

[57] Liang R,Zhang Y.Deep dissection of stemness-related hierarchies in hepatocellular carcinoma.J Transl Med2023;21:631 PMCID:PMC10505333

[58] Kan A,He M.MZF1 promotes tumour progression and resistance to anti-PD-L1 antibody treatment in hepatocellular carcinoma.JHEP Rep2024;6:100939 PMCID:PMC10701130

[59] Xu N,Chen Y.Downregulation of N4-acetylcytidine modification in myeloid cells attenuates immunotherapy and exacerbates hepatocellular carcinoma progression.Br J Cancer2024;130:201-12 PMCID:PMC10803308

[60] Wang L,Liang C.Targeting N6-methyladenosine reader YTHDF1 with siRNA boosts antitumor immunity in NASH-HCC by inhibiting EZH2-IL-6 axis.J Hepatol2023;79:1185-200

[61] Liu M,Liu X.Targeting monocyte-intrinsic enhancer reprogramming improves immunotherapy efficacy in hepatocellular carcinoma.Gut2020;69:365-79

[62] Xiong Z,Zhou J.Targeting PPAR-gamma counteracts tumour adaptation to immune-checkpoint blockade in hepatocellular carcinoma.Gut2023;72:1758-73 PMCID:PMC10423534

[63] Wang H,Xie DF,Yang T.LAPTM4B-mediated hepatocellular carcinoma stem cell proliferation and MDSC migration: implications for HCC progression and sensitivity to PD-L1 monoclonal antibody therapy.Cell Death Dis2024;15:165 PMCID:PMC10884007

[64] Conche C,Pešić M.Combining ferroptosis induction with MDSC blockade renders primary tumours and metastases in liver sensitive to immune checkpoint blockade.Gut2023;72:1774-82 PMCID:PMC10423492

[65] Wang S,Li T.Disruption of MerTK increases the efficacy of checkpoint inhibitor by enhancing ferroptosis and immune response in hepatocellular carcinoma.Cell Rep Med2024;5:101415 PMCID:PMC10897610

[66] Wen J,Wong CC.Targeting squalene epoxidase restores anti-PD-1 efficacy in metabolic dysfunction-associated steatohepatitis-induced hepatocellular carcinoma.Gut2024;73:2023-36 PMCID:PMC11671884

[67] Meng G,Chen A.Targeting aerobic glycolysis by dichloroacetate improves Newcastle disease virus-mediated viro-immunotherapy in hepatocellular carcinoma.Br J Cancer2020;122:111-20 PMCID:PMC6964686

[68] Kwong TT,Zhou JY.Chemotherapy-induced recruitment of myeloid-derived suppressor cells abrogates efficacy of immune checkpoint blockade.JHEP Rep2021;3:100224 PMCID:PMC7876565

[69] Ren Y,Guo Y.Melatonin enhances the efficacy of anti-PD-L1 by improving hypoxia in residual tumors after insufficient radiofrequency ablation.J Pharm Anal2024;14:100942 PMCID:PMC11388694

[70] Suthen S,Nguyen PHD.Hypoxia-driven immunosuppression by Treg and type-2 conventional dendritic cells in HCC.Hepatology2022;76:1329-44

[71] Wang Z,Li W.GDF15 induces immunosuppression via CD48 on regulatory T cells in hepatocellular carcinoma.J Immunother Cancer2021;9:e002787 PMCID:PMC8422483

[72] Luo X,Li S.SOX12 facilitates hepatocellular carcinoma progression and metastasis through promoting regulatory T-cells infiltration and immunosuppression.Adv Sci2024;11:e2310304 PMCID:PMC11423149

[73] Tan J,Fan W.Anti-PD-L1 antibody enhances curative effect of cryoablation via antibody-dependent cell-mediated cytotoxicity mediating PD-L1^highCD11b⁺ cells elimination in hepatocellular carcinoma.Acta Pharm Sin B2023;13:632-47 PMCID:PMC9978915

[74] Zhang PF,Huang XY.Cancer cell-derived exosomal circUHRF1 induces natural killer cell exhaustion and may cause resistance to anti-PD1 therapy in hepatocellular carcinoma.Mol Cancer2020;19:110 PMCID:PMC7320583

[75] Xiao R,Zhang J.Increased Siglec-9/Siglec-9L interactions on NK cells predict poor HCC prognosis and present a targetable checkpoint for immunotherapy.J Hepatol2024;80:792-804

[76] Heinrich B,Schäffer AA.The tumour microenvironment shapes innate lymphoid cells in patients with hepatocellular carcinoma.Gut2022;71:1161-75 PMCID:PMC8807808

[77] Hu Z,Zhao Y.Exosome-derived circCCAR1 promotes CD8 + T-cell dysfunction and anti-PD1 resistance in hepatocellular carcinoma.Mol Cancer2023;22:55 PMCID:PMC10024440

[78] Yu J,Hong J.TP53/mTORC1-mediated bidirectional regulation of PD-L1 modulates immune evasion in hepatocellular carcinoma.J Immunother Cancer2023;11:e007479 PMCID:PMC10689408

[79] Lv T,Yan W,Xu H.Targeting of GSDMD sensitizes HCC to anti-PD-1 by activating cGAS pathway and downregulating PD-L1 expression.J Immunother Cancer2022;10:e004763 PMCID:PMC9189836

[80] Weng J,Hu Z.Repolarization of immunosuppressive macrophages by targeting SLAMF7-regulated CCL2 signaling sensitizes hepatocellular carcinoma to immunotherapy.Cancer Res2024;84:1817-33

[81] Sung PS,Roh PR.Intrahepatic inflammatory IgA⁺PD-L1^high monocytes in hepatocellular carcinoma development and immunotherapy.J Immunother Cancer2022;10:e003618 PMCID:PMC9114848

[82] Cai J,Zhang F.Targeting SRSF10 might inhibit M2 macrophage polarization and potentiate anti-PD-1 therapy in hepatocellular carcinoma.Cancer Commun2024;44:1231-60 PMCID:PMC11570766

[83] Lao Y,Xu Z.Glutaryl-CoA dehydrogenase suppresses tumor progression and shapes an anti-tumor microenvironment in hepatocellular carcinoma.J Hepatol2024;81:847-61

[84] Wang S,Xu N.SULT2B1-CS-DOCK2 axis regulates effector T-cell exhaustion in HCC microenvironment.Hepatology2023;78:1064-78

[85] Seimiya T,Fujishiro M.Overcoming T-cell exhaustion: new therapeutic targets in HCC immunotherapy.Hepatology2023;78:1009-11

[86] Pan Y,Zhang X.METTL3 drives NAFLD-related hepatocellular carcinoma and is a therapeutic target for boosting immunotherapy.Cell Rep Med2023;4:101144 PMCID:PMC10439254

[87] Wang X,Chen X.System analysis based on the cancer-immunity cycle identifies ZNF207 as a novel immunotherapy target for hepatocellular carcinoma.J Immunother Cancer2022;10:e004414 PMCID:PMC8900045

[88] Pan B,Zhang X.Targeted inhibition of RBPJ transcription complex alleviates the exhaustion of CD8⁺ T cells in hepatocellular carcinoma.Commun Biol2023;6:123 PMCID:PMC9887061

[89] Wabitsch S,Kamenyeva O.Metformin treatment rescues CD8⁺ T-cell response to immune checkpoint inhibitor therapy in mice with NAFLD.J Hepatol2022;77:748-60 PMCID:PMC9391315

[90] Cai N,Ma Y.Targeting MMP9 in CTNNB1 mutant hepatocellular carcinoma restores CD8⁺ T cell-mediated antitumour immunity and improves anti-PD-1 efficacy.Gut2024;73:985-99 PMCID:PMC11103337

[91] Hu B,Ma X.IFNα potentiates anti-PD-1 efficacy by remodeling glucose metabolism in the hepatocellular carcinoma microenvironment.Cancer Discov2022;12:1718-41

[92] Wang X,Shen H,Lu X.Downregulation of TPX2 impairs the antitumor activity of CD8+ T cells in hepatocellular carcinoma.Cell Death Dis2022;13:223 PMCID:PMC8913637

[93] Huang J,Fang XN.FASN inhibition decreases MHC-I degradation and synergizes with PD-L1 checkpoint blockade in hepatocellular carcinoma.Cancer Res2024;84:855-71

[94] Shi Y,Liu S.Targeting PRMT3 impairs methylation and oligomerization of HSP60 to boost anti-tumor immunity by activating cGAS/STING signaling.Nat Commun2024;15:7930 PMCID:PMC11387718

[95] Song F,Liang XL.Anlotinib potentiates anti-PD1 immunotherapy via transferrin receptor-dependent CD8⁺ T-cell infiltration in hepatocellular carcinoma.Clin Transl Med2024;14:e1738 PMCID:PMC11296886

[96] Dal Bo M,Baboci L.New insights into the pharmacological, immunological, and CAR-T-cell approaches in the treatment of hepatocellular carcinoma.Drug Resist Updat2020;51:100702

[97] Li S,Wang K.Low-dose radiotherapy combined with dual PD-L1 and VEGFA blockade elicits antitumor response in hepatocellular carcinoma mediated by activated intratumoral CD8⁺ exhausted-like T cells.Nat Commun2023;14:7709 PMCID:PMC10673920

[98] Kikuchi H,Morita S.Increased CD8+ T-cell infiltration and efficacy for multikinase inhibitors after PD-1 blockade in hepatocellular carcinoma.J Natl Cancer Inst2022;114:1301-5 PMCID:PMC9468280

[99] Ke J,Liu F.In-situ-formed immunotherapeutic and hemostatic dual drug-loaded nanohydrogel for preventing postoperative recurrence of hepatocellular carcinoma.J Control Release2024;372:141-54

[100] Yu Z,Liu Y.Nano delivery of simvastatin targets liver sinusoidal endothelial cells to remodel tumor microenvironment for hepatocellular carcinoma.J Nanobiotechnology2022;20:9 PMCID:PMC8725360

[101] Zhang L,Zhou S.Endothelial DGKG promotes tumor angiogenesis and immune evasion in hepatocellular carcinoma.J Hepatol2024;80:82-98

[102] Tang B,Zhao Z.Diagnosis and prognosis models for hepatocellular carcinoma patient’s management based on tumor mutation burden.J Adv Res2021;33:153-65 PMCID:PMC8463909

[103] Greten TF,Korangy F.Biomarkers for immunotherapy of hepatocellular carcinoma.Nat Rev Clin Oncol2023;20:780-98

[104] Ao H,Jian Z.Liquid biopsy to identify biomarkers for immunotherapy in hepatocellular carcinoma.Biomark Res2021;9:91 PMCID:PMC8686238

[105] Hong JY,Sa JK.Hepatocellular carcinoma patients with high circulating cytotoxic T cells and intra-tumoral immune signature benefit from pembrolizumab: results from a single-arm phase 2 trial.Genome Med2022;14:1 PMCID:PMC8734300

[106] Anwanwan D,Singh S,Singh R.Challenges in liver cancer and possible treatment approaches.Biochim Biophys Acta Rev Cancer2020;1873:188314 PMCID:PMC6981221

[107] Sperandio RC,Miyamura BV.Hepatocellular carcinoma immunotherapy.Annu Rev Med2022;73:267-78

[108] Fulgenzi CAM,Airoldi C.Comparative efficacy of novel combination strategies for unresectable hepatocellular carcinoma: a network metanalysis of phase III trials.Eur J Cancer2022;174:57-67

[109] Llovet JM,Kelley RK.Molecular pathogenesis and systemic therapies for hepatocellular carcinoma.Nat Cancer2022;3:386-401 PMCID:PMC9060366

[110] Qin S, Chan SL, Gu S, et al; CARES-310 Study Group. 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;402:1133-46.

[111] Zhang S,Danilova L.Spatial transcriptomics analysis of neoadjuvant cabozantinib and nivolumab in advanced hepatocellular carcinoma identifies independent mechanisms of resistance and recurrence.Genome Med2023;15:72 PMCID:PMC10506285

[112] Llovet JM,Singal AG.Nonalcoholic steatohepatitis-related hepatocellular carcinoma: pathogenesis and treatment.Nat Rev Gastroenterol Hepatol2023;20:487-503

[113] Yang H,Yuan S.Self-delivery photothermal-boosted-nanobike multi-overcoming immune escape by photothermal/chemical/immune synergistic therapy against HCC.J Nanobiotechnology2024;22:137 PMCID:PMC10981284

[114] Yang SF,Liang JD.Neoantigen vaccination augments antitumor effects of anti-PD-1 on mouse hepatocellular carcinoma.Cancer Lett2023;563:216192

[115] Zheng Z,Han X.Idarubicin-loaded biodegradable microspheres enhance sensitivity to anti-PD1 immunotherapy in transcatheter arterial chemoembolization of hepatocellular carcinoma.Acta Biomater2023;157:337-51

[116] Chen Y,Shang H.Mechanism exploration of synergistic photo-immunotherapy strategy based on a novel exosome-like nanosystem for remodeling the immune microenvironment of HCC.Nano Converg2024;11:31 PMCID:PMC11324638

[117] Liu X,Wu H.Fibrotic immune microenvironment remodeling mediates superior anti-tumor efficacy of a nano-PD-L1 trap in hepatocellular carcinoma.Mol Ther2023;31:119-33 PMCID:PMC9840184

[118] Zhang Y,Min J.Biomimetic responsive nanoconverters with immune checkpoint blockade plus antiangiogenesis for advanced hepatocellular carcinoma treatment.ACS Appl Mater Interfaces2024;16:6894-907

[119] Ji G,Yao H.Precise delivery of obeticholic acid via nanoapproach for triggering natural killer T cell-mediated liver cancer immunotherapy.Acta Pharm Sin B2020;10:2171-82 PMCID:PMC7715527

[120] Sim T,Kwon SW.Magneto-activation and magnetic resonance imaging of natural killer cells labeled with magnetic nanocomplexes for the treatment of solid tumors.ACS Nano2021;15:12780-93

[121] Zhang BC,Luo BY.Triterpenoids-templated self-assembly nanosystem for biomimetic delivery of CRISPR/Cas9 based on the synergy of TLR-2 and ICB to enhance HCC immunotherapy.Acta Pharm Sin B2024;14:3205-17 PMCID:PMC11252477

[122] Lin Z,Wang P.Caveolin-mediated cytosolic delivery of spike nanoparticle enhances antitumor immunity of neoantigen vaccine for hepatocellular carcinoma.Theranostics2023;13:4166-81 PMCID:PMC10405843

[123] Hou G,Guo M.Hydrazide-manganese coordinated multifunctional nanoplatform for potentiating immunotherapy in hepatocellular carcinoma.J Colloid Interface Sci2022;628:968-83

[124] Carloni R,Rizzo A.Immune-based combination therapies for advanced hepatocellular carcinoma.J Hepatocell Carcinoma2023;10:1445-63 PMCID:PMC10493094

[125] Sun RX,Sun YS.GPC3-targeted CAR-T cells expressing GLUT1 or AGK exhibit enhanced antitumor activity against hepatocellular carcinoma.Acta Pharmacol Sin2024;45:1937-50 PMCID:PMC11336244

[126] Pang N,Qin L.IL-7 and CCL19-secreting CAR-T cell therapy for tumors with positive glypican-3 or mesothelin.J Hematol Oncol2021;14:118 PMCID:PMC8323212

[127] Makkouk A,Barca T.Off-the-shelf Vδ1 gamma delta T cells engineered with glypican-3 (GPC-3)-specific chimeric antigen receptor (CAR) and soluble IL-15 display robust antitumor efficacy against hepatocellular carcinoma.J Immunother Cancer2021;9:e003441 PMCID:PMC8679077

[128] Lu LL,Lin ZY.GPC3-IL7-CCL19-CAR-T primes immune microenvironment reconstitution for hepatocellular carcinoma therapy.Cell Biol Toxicol2023;39:3101-19

[129] Aggeletopoulou I,Triantos C.Chimeric antigen receptor T cell therapy for hepatocellular carcinoma: where do we stand?.Int J Mol Sci2024;25:2631 PMCID:PMC10932062