REFERENCES

1. Tan EY, Danpanichkul P, Yong JN, et al. Liver cancer in 2021: Global Burden of Disease study. J Hepatol. 2025;82:851-60.

2. Li Q, Ding C, Cao M, et al. Global epidemiology of liver cancer 2022: an emphasis on geographic disparities. Chin Med J. 2024;137:2334-42.

3. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74:229-63.

4. Du D, Liu C, Qin M, et al. Metabolic dysregulation and emerging therapeutical targets for hepatocellular carcinoma. Acta Pharm Sin B. 2022;12:558-80.

5. Deng Q, Huang Y, Zeng J, et al. Recent advancements in the small-molecule drugs for hepatocellular carcinoma (HCC): structure-activity relationships, pharmacological activities, and the clinical trials. Biomed Pharmacother. 2024;179:117343.

6. Sangro B, Chan SL, Meyer T, Reig M, El-Khoueiry A, Galle PR. Diagnosis and management of toxicities of immune checkpoint inhibitors in hepatocellular carcinoma. J Hepatol. 2020;72:320-41.

7. Ruiz de Galarreta M, Bresnahan E, Molina-Sánchez P, et al. β-catenin activation promotes immune escape and resistance to anti-PD-1 therapy in hepatocellular carcinoma. Cancer Discov. 2019;9:1124-41.

8. Zhou J, Wang W, Li Q. Potential therapeutic targets in the tumor microenvironment of hepatocellular carcinoma: reversing the protumor effect of tumor-associated macrophages. J Exp Clin Cancer Res. 2021;40:73.

9. Ho DW, Tsui YM, Chan LK, et al. Single-cell RNA sequencing shows the immunosuppressive landscape and tumor heterogeneity of HBV-associated hepatocellular carcinoma. Nat Commun. 2021;12:3684.

10. Song W, Li M, Liu W, et al. Role of immune cell homeostasis in research and treatment response in hepatocellular carcinoma. Clin Exp Med. 2025;25:42.

11. Yoshiji H, Kuriyama S, Yoshii J, et al. Involvement of the vascular endothelial growth factor receptor-1 in murine hepatocellular carcinoma development. J Hepatol. 2004;41:97-103.

12. Sieghart W, Hucke F, Peck-Radosavljevic M. Transarterial chemoembolization: modalities, indication, and patient selection. J Hepatol. 2015;62:1187-95.

13. McDermott DF, Huseni MA, Atkins MB, et al. Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nat Med. 2018;24:749-57.

14. Li D, Toh HC, Merle P, et al. Atezolizumab plus bevacizumab versus sorafenib for unresectable hepatocellular carcinoma: results from older adults enrolled in the IMbrave150 randomized clinical trial. Liver Cancer. 2022;11:558-71.

15. 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.

16. Kudo M. A paradigm change in the treatment strategy for hepatocellular carcinoma. Liver Cancer. 2020;9:367-77.

17. Zhu H, Chen XP, Zhang WG, Luo SF, Zhang BX. Expression and significance of new inhibitor of apoptosis protein survivin in hepatocellular carcinoma. World J Gastroenterol. 2005;11:3855-9.

18. Yang Y, Zhang Y, Iwamoto H, et al. Discontinuation of anti-VEGF cancer therapy promotes metastasis through a liver revascularization mechanism. Nat Commun. 2016;7:12680.

19. Liu WJ, Wang L, Zhou FM, et al. Elevated NOX4 promotes tumorigenesis and acquired EGFR-TKIs resistance via enhancing IL-8/PD-L1 signaling in NSCLC. Drug Resist Updat. 2023;70:100987.

20. Liu G, Zhou W, Li X, et al. Case report: complete response of primary massive hepatocellular carcinoma to anti-programmed death ligand-1 antibody following progression on anti-programmed death-1 antibody. Front Immunol. 2021;12:712351.

21. Sangro B, Chan SL, Kelley RK, et al; HIMALAYA investigators. Four-year overall survival update from the phase III HIMALAYA study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. Ann Oncol. 2024;35:448-57.

22. Sangro B, Galle PR, Kelley RK, et al. Patient-reported outcomes from the phase III HIMALAYA study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. J Clin Oncol. 2024;42:2790-9.

23. Abou-Alfa GK, Lau G, Kudo M, et al. Plain language summary of the HIMALAYA study: tremelimumab and durvalumab for unresectable hepatocellular carcinoma (liver cancer). Future Oncol. 2023;19:2505-16.

24. Akbay EA, Koyama S, Carretero J, et al. Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. Cancer Discov. 2013;3:1355-63.

25. Jing Y, Liu J, Ye Y, et al. Multi-omics prediction of immune-related adverse events during checkpoint immunotherapy. Nat Commun. 2020;11:4946.

26. Kim DJ, Anandh S, Null JL, et al. Priming a vascular-selective cytokine response permits CD8+ T-cell entry into tumors. Nat Commun. 2023;14:2122.

27. Sun X, Zhang Q, Mei J, Yang Z, Chen M, Liang T. Real-world efficiency of lenvatinib plus PD-1 blockades in advanced hepatocellular carcinoma: an exploration for expanded indications. BMC Cancer. 2022;22:293.

28. Llovet JM, Kudo M, Merle P, et al; LEAP-002 Investigators. Lenvatinib plus pembrolizumab versus lenvatinib plus placebo for advanced hepatocellular carcinoma (LEAP-002): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2023;24:1399-410.

29. Finn RS, Kudo M, Merle P, et al. Health-related quality of life analysis of the LEAP-002 study of lenvatinib plus pembrolizumab versus lenvatinib as first-line treatment for advanced hepatocellular carcinoma. ESMO Open. 2025;10:105065.

30. Yu X, Wei C, Cui R, Jiang O. Lenvatinib plus immune checkpoint inhibitors versus lenvatinib monotherapy as treatment for advanced hepatocellular carcinoma: a meta-analysis. Int J Clin Exp Pathol. 2023;16:321-31.

31. Galle PR, Decaens T, Kudo M, 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. JCO. 2024;42:LBA4008.

32. Cheng AL, Qin S, Ikeda M, et al. Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma. J Hepatol. 2022;76:862-73.

33. Abou-Alfa GK, Lau G, Kudo M, et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evid. 2022;1:EVIDoa2100070.

34. Yau T, Galle PR, Decaens T, et al; CheckMate 9DW investigators. Nivolumab plus ipilimumab versus lenvatinib or sorafenib as first-line treatment for unresectable hepatocellular carcinoma (CheckMate 9DW): an open-label, randomised, phase 3 trial. Lancet. 2025;405:1851-64.

35. Ricke J, Klümpen HJ, Amthauer H, et al. Impact of combined selective internal radiation therapy and sorafenib on survival in advanced hepatocellular carcinoma. J Hepatol. 2019;71:1164-74.

36. Duffy AG, Ulahannan SV, Makorova-Rusher O, et al. Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma. J Hepatol. 2017;66:545-51.

37. Sangro B, Kudo M, Erinjeri JP, et al; EMERALD-1 Investigators. 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;405:216-32.

38. Llovet JM, Vogel A, Madoff DC, et al. Randomized phase 3 LEAP-012 study: transarterial chemoembolization with or without lenvatinib plus pembrolizumab for intermediate-stage hepatocellular carcinoma not amenable to curative treatment. Cardiovasc Intervent Radiol. 2022;45:405-12.

39. Kudo M, Ren Z, Guo Y, et al; LEAP-012 investigators. 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;405:203-15.

40. Singal AG, Rich NE, Mehta N, et al. Direct-acting antiviral therapy for hepatitis C virus infection is associated with increased survival in patients with a history of hepatocellular carcinoma. Gastroenterology. 2019;157:1253-63.e2.

41. Ma J, Xin Y, Wang Q, Ding L. Roles of cGAS-STING pathway in radiotherapy combined with immunotherapy for hepatocellular carcinoma. Mol Cancer Ther. 2024;23:447-53.

42. Zhao S, Zhang Y, Lu X, et al. CDC20 regulates the cell proliferation and radiosensitivity of P53 mutant HCC cells through the Bcl-2/Bax pathway. Int J Biol Sci. 2021;17:3608-21.

43. Zhao S, Wei C, Tang H, et al. Elevated DNA polymerase delta 1 expression correlates with tumor progression and immunosuppressive tumor microenvironment in hepatocellular carcinoma. Front Oncol. 2021;11:736363.

44. Rao Q, Zuo B, Lu Z, et al. Tumor-derived exosomes elicit tumor suppression in murine hepatocellular carcinoma models and humans in vitro. Hepatology. 2016;64:456-72.

45. Tang X, Ding M, Lu B, et al. Outcomes of ultrasound-guided percutaneous microwave ablation versus surgical resection for symptomatic large hepatic hemangiomas. Int J Hyperthermia. 2019;36:632-9.

46. Nam JY, Lee YB, Lee JH, et al. A prognostic prediction model of transarterial radioembolization in hepatocellular carcinoma: SNAP-HCC. Dig Dis Sci. 2022;67:329-36.

47. Xu T, Wang W, Bao R, et al. Anti-PD-1 plus anti-angiogenesis combined with chemotherapy in patients with HER2-negative advanced or metastatic gastric cancer: a multi-institutional retrospective study. J Gastrointest Oncol. 2023;14:175-86.

48. El-Khoueiry AB, Hanna DL, Llovet J, Kelley RK. Cabozantinib: an evolving therapy for hepatocellular carcinoma. Cancer Treat Rev. 2021;98:102221.

49. Kimura T, Kato Y, Ozawa Y, et al. Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hepa1-6 hepatocellular carcinoma model. Cancer Sci. 2018;109:3993-4002.

50. Cucchetti A, Serenari M, Sposito C, et al. Including mRECIST in the Metroticket 2.0 criteria improves prediction of hepatocellular carcinoma-related death after liver transplant. J Hepatol. 2020;73:342-8.

51. Singal AG, Yarchoan M, Yopp A, Sapisochin G, Pinato DJ, Pillai A. Neoadjuvant and adjuvant systemic therapy in HCC: current status and the future. Hepatol Commun. 2024;8:e0430.

52. Ho WJ, Zhu Q, Durham J, et al. Neoadjuvant cabozantinib and nivolumab converts locally advanced hcc into resectable disease with enhanced antitumor immunity. Nat Cancer. 2021;2:891-903.

53. Goodsell KE, Tao AJ, Park JO. Neoadjuvant therapy for hepatocellular carcinoma-priming precision innovations to transform HCC treatment. Front Surg. 2025;12:1531852.

54. Dikilitas M. Why adjuvant and neoadjuvant therapy failed in HCC. Can the new immunotherapy be expected to be better? J Gastrointest Cancer. 2020;51:1193-6.

55. Batra SA, Rathi P, Guo L, et al. Glypican-3-specific CAR T cells coexpressing IL15 and IL21 have superior expansion and antitumor activity against hepatocellular carcinoma. Cancer Immunol Res. 2020;8:309-20.

56. Makkouk A, Yang XC, Barca T, et al. 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 Cancer. 2021;9:e003441.

57. Zhang Q, Fu Q, Cao W, et al. Phase I study of C-CAR031, a GPC3-specific TGFβRIIDN armored autologous CAR-T, in patients with advanced hepatocellular carcinoma (HCC). JCO. 2024;42:4019.

58. Fu Q, Zheng Y, Fang W, et al. RUNX-3-expressing CAR T cells targeting glypican-3 in patients with heavily pretreated advanced hepatocellular carcinoma: a phase I trial. EClinicalMedicine. 2023;63:102175.

59. Huhn GD, Wilkin A, Mussini C, et al; AMBER and EMERALD study groups. Phase I study of Ori-C101, an armored GPC3-directed CAR-T, in patients with advanced hepatocellular carcinoma (HCC). J Clin Oncol. 2025;43:4084.

60. Liu WN, Harden SL, Tan SLW, et al. Single-cell RNA sequencing reveals anti-tumor potency of CD56+ NK cells and CD8+ T cells in humanized mice via PD-1 and TIGIT co-targeting. Mol Ther. 2024;32:3895-914.

61. Finn RS, Ryoo BY, Hsu CH, 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;26:214-26.

62. Badhrinarayanan S, Cotter C, Zhu H, Lin YC, Kudo M, Li D. IMbrave152/SKYSCRAPER-14: a phase III study of atezolizumab, bevacizumab and tiragolumab in advanced hepatocellular carcinoma. Future Oncol. 2024;20:2049-57.

63. Wang J, Cao Y, Tian Y, Dai C, Jin T, Xu F. A novel prognostic nomogram based on TIGIT and NKG2A can predict relapse-free survival of hepatocellular carcinoma after hepatectomy. Cancer Med. 2024;13:e70419.

64. Yarchoan M, Gane EJ, Marron TU, et al. Personalized neoantigen vaccine and pembrolizumab in advanced hepatocellular carcinoma: a phase 1/2 trial. Nat Med. 2024;30:1044-53.

65. Gao Q, Zhu H, Dong L, et al. Integrated proteogenomic characterization of HBV-related hepatocellular carcinoma. Cell. 2019;179:561-77.e22.

66. Dadey RE, Li R, Griner J, et al. Multiomics identifies tumor-intrinsic SREBP1 driving immune exclusion in hepatocellular carcinoma. J Immunother Cancer. 2025;13:e011537.

67. Perugorria MJ, Olaizola P, Labiano I, et al. Wnt-β-catenin signalling in liver development, health and disease. Nat Rev Gastroenterol Hepatol. 2019;16:121-36.

68. Milosevic I, Vujovic A, Barac A, et al. Gut-liver axis, gut microbiota, and its modulation in the management of liver diseases: a review of the literature. Int J Mol Sci. 2019;20:395.

69. Zhang X, Coker OO, Chu ES, et al. Dietary cholesterol drives fatty liver-associated liver cancer by modulating gut microbiota and metabolites. Gut. 2021;70:761-74.

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