Progress and bottleneck issues on immunotherapy of hepatocellular carcinoma_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

 ZHUO Shijie , CHEN Ke , LUO Cong

Department of Hepatobiliary, Pancreatic and Splenic Surgery, Zizhong People’s Hospital, Zizhong, Sichuan 641200, P. R. China;

Corresponding?author：

ZHUO Shijie, Email: zhuoshijie911@163.com

Keywords：

hepatocellular carcinoma; immunotherapy

DOI：

10.7507/1007-9424.202512087

Video：

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Objective To systematically summarize recent research advances in immunotherapy for hepatocellular carcinoma (HCC) and analyze key challenges in this field. Methods Through a systematic review of literature, this study concludes researches on the application of immune checkpoint inhibitors in HCC treatment, combination therapy strategies, and mechanisms of drug resistance. Results Immune therapies, particularly immune checkpoint inhibitors, have significantly transformed the treatment landscape of hepatocellular carcinoma. Dual immune combination therapies and immunotherapies combined with anti-angiogenic agents have become new treatment strategies. However, high heterogeneity of HCC, complex tumor microenvironment and the resulting acquired drug resistance remain major which affect the efficacy of immunotherapy. Conclusion Although immunotherapy bring new hope in HCC patients, further in-depth investigation on resistance mechanisms and develop novel combination treatment strategies are needed to break through the bottleneck of current immunotherapy.

Citation： ZHUO Shijie, CHEN Ke, LUO Cong. Progress and bottleneck issues on immunotherapy of hepatocellular carcinoma. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2026, 33(3): 338-343. doi: 10.7507/1007-9424.202512087 Copy

1.	Shin SK, Mishima Y, Lee Y, et al. Current landscape of adoptive cell therapy and challenge to develop “off-the-shelf” therapy for hepatocellular carcinoma. J Gastroenterol Hepatol, 2025, 40(4): 791-807.
2.	Hu HH, Wang X, Lan B, et al. Glucose starvation mimetic aldometanib removes immune barriers permitting mice with hepatocellular carcinoma to live to normal ages. Cell Res, 2025, 35(12): 934-953.
3.	中華人民共和國國家衛生健康委員會醫政司. 原發性肝癌診療指南 (2024年版). 協和醫學雜志, 2024, 15(3): 532-559.
4.	Shek D, Read SA, Nagrial A, et al. Immune-checkpoint inhibitors for advanced hepatocellular carcinoma: a synopsis of response rates. Oncologist, 2021, 26(7): e1216-e1225.
5.	Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science, 2018, 359(6382): 1350-1355.
6.	Miwa C, Ogasawara S, Yonemoto T, et al. Durvalumab monotherapy in complex advanced hepatocellular carcinoma: a real-world study of patients ineligible for combination immunotherapy. Cancer Med, 2025, 14(5): e70642. doi: 10.1002/cam4.70642.
7.	Melero I, Yau T, Kang YK, 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.
8.	Yau T, Galle PR, Decaens T, et al. 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(10492): 1851-1864.
9.	Abou-Alfa GK, Lau G, Kudo M, et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evid, 2022, 1(8): EVIDoa2100070. doi: 10.1056/EVIDoa2100070.
10.	Gao X, Xu N, Li Z, et al. Safety and antitumour activity of cadonilimab, an anti-PD-1/CTLA-4 bispecific antibody, for patients with advanced solid tumours (COMPASSION-03): a multicentre, open-label, phase 1b/2 trial. Lancet Oncol, 2023, 24(10): 1134-1146.
11.	Remash D, Prince DS, McKenzie C, et al. Immune checkpoint inhibitor-related hepatotoxicity: a review. World J Gastroenterol, 2021, 27(32): 5376-5391.
12.	Lee WS, Yang H, Chon HJ, et al. Combination of anti-angiogenic therapy and immune checkpoint blockade normalizes vascular-immune crosstalk to potentiate cancer immunity. Exp Mol Med, 2020, 52(9): 1475-1485.
13.	Kelley RK, Rimassa L, Cheng A, et al. Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (cosmic-312): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol, 2022, 23(8): 995-1008.
14.	Hu Z, Yang Z, Fu Z, et al. Efficacy and safety of atezolizumab-bevacizumab vs pembrolizumab-lenvatinib in unresectable hepatocellular carcinoma: a retrospective, cohort study. Front Immunol, 2024, 15: 1472870. doi: 10.3389/fimmu.2024.1472870.
15.	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(4): 862-873.
16.	Ren Z, Xu J, Bai Y, 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): 977-990.
17.	Li H, Qin S, Liu Y, et al. Camrelizumab combined with FOLFOX4 regimen as first-line therapy for advanced hepatocellular carcinomas: a sub-cohort of a multicenter phase Ⅰb/Ⅱ study. Drug Des Devel Ther, 2021, 15: 1873-1882.
18.	Qin S, Chen M, Cheng AL, et al. Atezolizumab plus bevacizumab versus active surveillance in patients with resected or ablated high-risk hepatocellular carcinoma (IMbrave050): a randomised, open-label, multicentre, phase 3 trial. Lancet, 2023, 402(10415): 1835-1847.
19.	Yuan Y, He W, Yang Z, et al. TACE-HAIC combined with targeted therapy and immunotherapy versus TACE alone for hepatocellular carcinoma with portal vein tumour thrombus: a propensity score matching study. Int J Surg, 2023, 109(5): 1222-1230.
20.	Kroeze SGC, Pavic M, Stellamans K, et al. Metastases-directed stereotactic body radiotherapy in combination with targeted therapy or immunotherapy: systematic review and consensus recommendations by the EORTC-ESTRO OligoCare consortium. Lancet Oncol, 2023, 24(3): e121-e132.
21.	Ji Q, Fu Y, Zhu X, et al. Effect of RFA and TACE combined with postoperative cytokine-induced killer cell immunotherapy in primary hepatocellular carcinoma. J BUON. 2021, 26(1): 235-242.
22.	Zhou Y, Lin F, Wan T, et al. ZEB1 enhances Warburg effect to facilitate tumorigenesis and metastasis of HCC by transcriptionally activating PFKM. Theranostics, 2021, 11(12): 5926-5938.
23.	Liu S, Pan Y, Liu W, et al. Lactylation-driven MVP upregulation boosts immunotherapy resistance by inhibiting PD-L1 degradation in hepatocellular carcinoma. J Immunother Cancer, 2025, 13(9): e012230. doi: 10.1136/jitc-2025-012230.
24.	Hao X, Zheng Z, Liu H, et al. 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 Biol. 2022, 102463. doi: 10.1016/j.redox.2022.102463.
25.	Liu YT, Wang YL, Wang S, et al. Turning cold tumors into hot tumors to ignite immunotherapy. Mol Cancer, 2025, 24(1): 254. doi: 10.1186/s12943-025-02477-6.
26.	Reinfeld BI, Madden MZ, Wolf MM, et al. Cell-programmed nutrient partitioning in the tumour microenvironment. Nature, 2021, 593(7858): 282-288.
27.	Liang XH, Chen XY, Yan Y, et al. Targeting metabolism to enhance immunotherapy within tumor microenvironment. Acta Pharmacol Sin, 2024, 45(10): 2011-2022.
28.	Scharping NE, Menk AV, Moreci RS, et al. The tumor microenvironment represses T cell mitochondrial biogenesis to drive intratumoral T cell metabolic insufficiency and dysfunction. Immunity, 2016, 45(2): 374-388.
29.	Yasukawa K, Shimada S, Akiyama Y, et al. ACVR2A attenuation impacts lactate production and hyperglycolytic conditions attracting regulatory T cells in hepatocellular carcinoma. Cell Rep Med, 2025, 6(4): 102038. doi: 10.1016/j.xcrm.2025.102038.
30.	Shin DS, Zaretsky JM, Escuin-Ordinas H, et al. Primary resistance to PD-1 blockade mediated by JAK1/2 mutations. Cancer Discov, 2017, 7(2): 188-201.
31.	Chang JQ, Guo Y, Yuan WJ, et al. HLA-DR⁺ tumor cells show an association with a distinct immune microenvironment and CD8⁺ T-cell exhaustion in HBV-associated hepatocellular carcinoma. Adv Sci (Weinh), 2025, 12(30): e02979. doi: 10.1002/advs.202502979.
32.	Myers S, Neyroud-Caspar I, Spahr L, et al. NAFLD and MAFLD as emerging causes of HCC: a populational study. JHEP Rep, 2021, 3(2): 100231. doi: 10.1016/j.jhepr.2021.100231.
33.	Osna NA, Rasineni K, Ganesan M, et al. Pathogenesis of alcohol-associated liver disease. J Clin Exp Hepatol, 2022, 12(6): 1492-1513.
34.	Finn RS, Ryoo B, Hsu C, 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.
35.	Guo Z, Liu Y, Ling Q, et al. Pretransplant use of immune checkpoint inhibitors for hepatocellular carcinoma: a multicenter, retrospective cohort study. Am J Transplant, 2024, 24(10): 1837-1856.
36.	Pallozzi M, Di Tommaso N, Maccauro V, Santopaolo F, Gasbarrini A, Ponziani FR, et al. Non-invasive biomarkers for immunotherapy in patients with hepatocellular carcinoma: current knowledge and future perspectives. Cancers (Basel), 2022, 14(19): 4631. doi: 10.3390/cancers14194631.
37.	Albarrán V, San Román M, Pozas J, et al. Adoptive T cell therapy for solid tumors: current landscape and future challenges. Front Immunol, 2024, 15: 1352805. doi: 10.3389/fimmu.2024.1352805.

1. Shin SK, Mishima Y, Lee Y, et al. Current landscape of adoptive cell therapy and challenge to develop “off-the-shelf” therapy for hepatocellular carcinoma. J Gastroenterol Hepatol, 2025, 40(4): 791-807.
2. Hu HH, Wang X, Lan B, et al. Glucose starvation mimetic aldometanib removes immune barriers permitting mice with hepatocellular carcinoma to live to normal ages. Cell Res, 2025, 35(12): 934-953.
3. 中華人民共和國國家衛生健康委員會醫政司. 原發性肝癌診療指南 (2024年版). 協和醫學雜志, 2024, 15(3): 532-559.
4. Shek D, Read SA, Nagrial A, et al. Immune-checkpoint inhibitors for advanced hepatocellular carcinoma: a synopsis of response rates. Oncologist, 2021, 26(7): e1216-e1225.
5. Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science, 2018, 359(6382): 1350-1355.
6. Miwa C, Ogasawara S, Yonemoto T, et al. Durvalumab monotherapy in complex advanced hepatocellular carcinoma: a real-world study of patients ineligible for combination immunotherapy. Cancer Med, 2025, 14(5): e70642. doi: 10.1002/cam4.70642.
7. Melero I, Yau T, Kang YK, 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.
8. Yau T, Galle PR, Decaens T, et al. 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(10492): 1851-1864.
9. Abou-Alfa GK, Lau G, Kudo M, et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evid, 2022, 1(8): EVIDoa2100070. doi: 10.1056/EVIDoa2100070.
10. Gao X, Xu N, Li Z, et al. Safety and antitumour activity of cadonilimab, an anti-PD-1/CTLA-4 bispecific antibody, for patients with advanced solid tumours (COMPASSION-03): a multicentre, open-label, phase 1b/2 trial. Lancet Oncol, 2023, 24(10): 1134-1146.
11. Remash D, Prince DS, McKenzie C, et al. Immune checkpoint inhibitor-related hepatotoxicity: a review. World J Gastroenterol, 2021, 27(32): 5376-5391.
12. Lee WS, Yang H, Chon HJ, et al. Combination of anti-angiogenic therapy and immune checkpoint blockade normalizes vascular-immune crosstalk to potentiate cancer immunity. Exp Mol Med, 2020, 52(9): 1475-1485.
13. Kelley RK, Rimassa L, Cheng A, et al. Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (cosmic-312): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol, 2022, 23(8): 995-1008.
14. Hu Z, Yang Z, Fu Z, et al. Efficacy and safety of atezolizumab-bevacizumab vs pembrolizumab-lenvatinib in unresectable hepatocellular carcinoma: a retrospective, cohort study. Front Immunol, 2024, 15: 1472870. doi: 10.3389/fimmu.2024.1472870.
15. 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(4): 862-873.
16. Ren Z, Xu J, Bai Y, 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): 977-990.
17. Li H, Qin S, Liu Y, et al. Camrelizumab combined with FOLFOX4 regimen as first-line therapy for advanced hepatocellular carcinomas: a sub-cohort of a multicenter phase Ⅰb/Ⅱ study. Drug Des Devel Ther, 2021, 15: 1873-1882.
18. Qin S, Chen M, Cheng AL, et al. Atezolizumab plus bevacizumab versus active surveillance in patients with resected or ablated high-risk hepatocellular carcinoma (IMbrave050): a randomised, open-label, multicentre, phase 3 trial. Lancet, 2023, 402(10415): 1835-1847.
19. Yuan Y, He W, Yang Z, et al. TACE-HAIC combined with targeted therapy and immunotherapy versus TACE alone for hepatocellular carcinoma with portal vein tumour thrombus: a propensity score matching study. Int J Surg, 2023, 109(5): 1222-1230.
20. Kroeze SGC, Pavic M, Stellamans K, et al. Metastases-directed stereotactic body radiotherapy in combination with targeted therapy or immunotherapy: systematic review and consensus recommendations by the EORTC-ESTRO OligoCare consortium. Lancet Oncol, 2023, 24(3): e121-e132.
21. Ji Q, Fu Y, Zhu X, et al. Effect of RFA and TACE combined with postoperative cytokine-induced killer cell immunotherapy in primary hepatocellular carcinoma. J BUON. 2021, 26(1): 235-242.
22. Zhou Y, Lin F, Wan T, et al. ZEB1 enhances Warburg effect to facilitate tumorigenesis and metastasis of HCC by transcriptionally activating PFKM. Theranostics, 2021, 11(12): 5926-5938.
23. Liu S, Pan Y, Liu W, et al. Lactylation-driven MVP upregulation boosts immunotherapy resistance by inhibiting PD-L1 degradation in hepatocellular carcinoma. J Immunother Cancer, 2025, 13(9): e012230. doi: 10.1136/jitc-2025-012230.
24. Hao X, Zheng Z, Liu H, et al. 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 Biol. 2022, 102463. doi: 10.1016/j.redox.2022.102463.
25. Liu YT, Wang YL, Wang S, et al. Turning cold tumors into hot tumors to ignite immunotherapy. Mol Cancer, 2025, 24(1): 254. doi: 10.1186/s12943-025-02477-6.
26. Reinfeld BI, Madden MZ, Wolf MM, et al. Cell-programmed nutrient partitioning in the tumour microenvironment. Nature, 2021, 593(7858): 282-288.
27. Liang XH, Chen XY, Yan Y, et al. Targeting metabolism to enhance immunotherapy within tumor microenvironment. Acta Pharmacol Sin, 2024, 45(10): 2011-2022.
28. Scharping NE, Menk AV, Moreci RS, et al. The tumor microenvironment represses T cell mitochondrial biogenesis to drive intratumoral T cell metabolic insufficiency and dysfunction. Immunity, 2016, 45(2): 374-388.
29. Yasukawa K, Shimada S, Akiyama Y, et al. ACVR2A attenuation impacts lactate production and hyperglycolytic conditions attracting regulatory T cells in hepatocellular carcinoma. Cell Rep Med, 2025, 6(4): 102038. doi: 10.1016/j.xcrm.2025.102038.
30. Shin DS, Zaretsky JM, Escuin-Ordinas H, et al. Primary resistance to PD-1 blockade mediated by JAK1/2 mutations. Cancer Discov, 2017, 7(2): 188-201.
31. Chang JQ, Guo Y, Yuan WJ, et al. HLA-DR⁺ tumor cells show an association with a distinct immune microenvironment and CD8⁺ T-cell exhaustion in HBV-associated hepatocellular carcinoma. Adv Sci (Weinh), 2025, 12(30): e02979. doi: 10.1002/advs.202502979.
32. Myers S, Neyroud-Caspar I, Spahr L, et al. NAFLD and MAFLD as emerging causes of HCC: a populational study. JHEP Rep, 2021, 3(2): 100231. doi: 10.1016/j.jhepr.2021.100231.
33. Osna NA, Rasineni K, Ganesan M, et al. Pathogenesis of alcohol-associated liver disease. J Clin Exp Hepatol, 2022, 12(6): 1492-1513.
34. Finn RS, Ryoo B, Hsu C, 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.
35. Guo Z, Liu Y, Ling Q, et al. Pretransplant use of immune checkpoint inhibitors for hepatocellular carcinoma: a multicenter, retrospective cohort study. Am J Transplant, 2024, 24(10): 1837-1856.
36. Pallozzi M, Di Tommaso N, Maccauro V, Santopaolo F, Gasbarrini A, Ponziani FR, et al. Non-invasive biomarkers for immunotherapy in patients with hepatocellular carcinoma: current knowledge and future perspectives. Cancers (Basel), 2022, 14(19): 4631. doi: 10.3390/cancers14194631.
37. Albarrán V, San Román M, Pozas J, et al. Adoptive T cell therapy for solid tumors: current landscape and future challenges. Front Immunol, 2024, 15: 1352805. doi: 10.3389/fimmu.2024.1352805.

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Progress and bottleneck issues on immunotherapy of hepatocellular carcinoma

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