Current research landscape of targeted therapy and immunotherapy for intermediate to advanced hepatocellular carcinoma_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

SU Yuhao ¹ , LIANG Yuxin ¹ ,  HUANG Xiaolun ²

1. School of Medicine, University of Electronic Science and Technology of China, Chengdu 610054, P. R. China;
2. Department of Hepatobiliary and Pancreatic Surgery, Liver Transplantation Center, Sichuan Cancer Hospital, Affiliated Cancer Hospital, University of Electronic Science and Technology, Chengdu 610042, P. R. China;

Corresponding?author：

HUANG Xiaolun, Email: huangxiaolun@med.uestc.edu.cn

Keywords：

hepatocellular carcinoma; targeted therapy; immune checkpoint inhibitor; combination therapy

DOI：

10.7507/1007-9424.202601111

Video：

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This article briefly introduces the multifactorial and multistep pathogenesis of hepatocellular carcinoma (HCC), as well as the synergistic mechanisms underlying targeted therapy and immunotherapy. It systematically reviews advances in drug therapy for intermediate to advanced HCC, covering the efficacy and limitations of targeted agents (e.g., multi-kinase inhibitors) and immune checkpoint inhibitor monotherapies, and highlights how combination strategies (such as the integration of targeted and immunotherapeutic drugs and dual immunotherapy) have evolved into new first-line treatment standards. Meanwhile, the article summarizes the potential applications and recent progress of targeted and immunotherapeutic drugs in perioperative adjuvant therapy. Furthermore, it outlines the spectrum of treatment-related adverse events, particularly immune-related adverse events and common toxicities associated with targeted agents, along with summarized principles for risk management. It points out that future efforts should focus on exploring biomarkers to precisely identify patient populations likely to benefit, optimizing treatment sequences and combination regimens, and strengthening comprehensive safety management throughout the entire treatment process, all while maintaining focus on enhancing therapeutic efficacy.

Citation： SU Yuhao, LIANG Yuxin, HUANG Xiaolun. Current research landscape of targeted therapy and immunotherapy for intermediate to advanced hepatocellular carcinoma. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2026, 33(3): 299-309. doi: 10.7507/1007-9424.202601111 Copy

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2. 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(3): 229-263.
3. 陳倩倩, 芮法娟, 倪文婧, 等. 原發性肝癌的流行病學及其危險因素研究進展. 中國全科醫學, 2024, 27(6): 637-642.
4. Singal AG, Kanwal F, Llovet JM. Global trends in hepatocellular carcinoma epidemiology: implications for screening, prevention and therapy. Nat Rev Clin Oncol, 2023, 20(12): 864-884.
5. Singal AG, Kudo M, Bruix J. Breakthroughs in hepatocellular carcinoma therapies. Clin Gastroenterol Hepatol, 2023, 21(8): 2135-2149.
6. Du D, Liu C, Qin M, et al. Metabolic dysregulation and emerging therapeutical targets for hepatocellular carcinoma. Acta Pharm Sin B, 2022, 12(2): 558-580.
7. De Martin E, Fulgenzi CAM, Celsa C, et al. Immune checkpoint inhibitors and the liver: balancing therapeutic benefit and adverse events. Gut, 2025, 74(7): 1165-1177.
8. Luo X, He X, Zhang X, et al. Hepatocellular carcinoma: signaling pathways, targeted therapy, and immunotherapy. MedComm (2020), 2024, 5(2): e474. doi: 10.1002/mco2.474.
9. Wong KM, King GG, Harris WP. The treatment landscape of advanced hepatocellular carcinoma. Curr Oncol Rep, 2022, 24(7): 917-927.
10. Liu M, Jiang L, Guan XY. The genetic and epigenetic alterations in human hepatocellular carcinoma: a recent update. Protein Cell, 2014, 5(9): 673-691.
11. Lin HY, Jeon AJ, Chen K, et al. The epigenetic basis of hepatocellular carcinoma—mechanisms and potential directions for biomarkers and therapeutics. Br J Cancer, 2025, 132(10): 869-887.
12. Bueloni B, Garcia Fernandez de Barrena M, Avila MA, et al. Epigenetic mechanisms involved in hepatocellular carcinoma development and progression. eGastroenterology, 2025, 3(2): e100186. doi: 10.1136/egastro-2025-100186.
13. Zhao LH, Liu X, Yan HX, et al. Genomic and oncogenic preference of HBV integration in hepatocellular carcinoma. Nat Commun, 2016, 7: 12992. doi: 10.1038/ncomms12992.
14. Sze KM, Ho DW, Chiu YT, et al. Hepatitis B virus-telomerase reverse transcriptase promoter integration harnesses host ELF4, resulting in telomerase reverse transcriptase gene transcription in hepatocellular carcinoma. Hepatology, 2021, 73(1): 23-40.
15. Jahan S, Ashfaq UA, Qasim M, et al. Hepatitis C virus to hepatocellular carcinoma. Infect Agent Cancer, 2012, 7(1): 2. doi: 10.1186/1750-9378-7-2.
16. Loomba R, Friedman SL, Shulman GI. Mechanisms and disease consequences of nonalcoholic fatty liver disease. Cell, 2021, 184(10): 2537-2564.
17. Rada P, González-Rodríguez á, García-Monzón C, et al. Understanding lipotoxicity in NAFLD pathogenesis: is CD36 a key driver?. Cell Death Dis, 2020, 11(9): 802. doi: 10.1038/s41419-020-03003-w.
18. Petagine L, Zariwala MG, Somavarapu S, et al. Oxidative stress in a cellular model of alcohol-related liver disease: protection using curcumin nanoformulations. Sci Rep, 2025, 15(1): 7752. doi: 10.1038/s41598-025-91139-0.
19. Xu J, Lin H, Wu G, et al. IL-6/STAT3 is a promising therapeutic target for hepatocellular carcinoma. Front Oncol, 2021, 11: 760971. doi: 10.3389/fonc.2021.760971.
20. Guo Y, Xiao Z, Yang L, et al. Hypoxia-inducible factors in hepatocellular carcinoma (Review). Oncol Rep, 2020, 43(1): 3-15.
21. Al-Awadhi SSA, Patil P, Shetty P, et al. Potential role of epidermal growth factor receptors (EGFR) signaling in the pathogenesis and management of hepatocellular carcinoma. Bioimpacts, 2025, 5: 30905. doi: 10.34172/bi.30905.
22. Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature, 2000, 407(6801): 249-257.
23. Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science, 2005, 307(5706): 58-62.
24. Gabrilovich D, Ishida T, Oyama T, et al. Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood, 1998, 92(11): 4150-4166.
25. Motz GT, Coukos G. The parallel lives of angiogenesis and immunosuppression: cancer and other tales. Nat Rev Immunol, 2011, 11(10): 702-711.
26. Baessler A, Vignali DAA. T cell exhaustion. Annu Rev Immunol, 2024, 42(1): 179-206.
27. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer, 2012, 12(4): 252-264.
28. Xia S, Pan Y, Liang Y, et al. The microenvironmental and metabolic aspects of sorafenib resistance in hepatocellular carcinoma. EBioMedicine, 2020, 51: 102610. doi: 10.1016/j.ebiom.2019.102610.
29. Rimassa L, Santoro A. Sorafenib therapy in advanced hepatocellular carcinoma: the SHARP trial. Expert Rev Anticancer Ther, 2009, 9(6): 739-745.
30. Kong FH, Ye QF, Miao XY, et al. Current status of sorafenib nanoparticle delivery systems in the treatment of hepatocellular carcinoma. Theranostics, 2021, 11(11): 5464-5490.
31. Hsu CH, Shen YC, Shao YY, et al. Sorafenib in advanced hepatocellular carcinoma: current status and future perspectives. J Hepatocell Carcinoma, 2014, 1: 85-99.
32. Zhu AX, Park JO, Ryoo BY, et al. Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol, 2015, 16(7): 859-870.
33. Zhu AX, Kang YK, Yen CJ, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol, 2019, 20(2): 282-296.
34. Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet, 2017, 389(10064): 56-66.
35. Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet, 2018, 391(10126): 1163-1173.
36. Peng Z, Fan W, Zhu B, et al. Lenvatinib combined with transarterial chemoembolization as first-line treatment for advanced hepatocellular carcinoma: a phase Ⅲ, randomized clinical trial (LAUNCH). J Clin Oncol, 2023, 41(1): 117-127.
37. Abou-Alfa GK, Meyer T, Cheng AL, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med, 2018, 379(1): 54-63.
38. Qin S, Li Q, Gu S, et al. Apatinib as second-line or later therapy in patients with advanced hepatocellular carcinoma (AHELP): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Gastroenterol Hepatol, 2021, 6(7): 559-568.
39. Yu WC, Zhang KZ, Chen SG, et al. Efficacy and safety of apatinib in patients with intermediate/advanced hepatocellular carcinoma: a prospective observation study. Medicine (Baltimore), 2018, 97(3): e9704. doi: 10.1097/MD.0000000000009704.
40. Qin S, Bi F, Gu S, et al. Donafenib versus sorafenib in first-line treatment of unresectable or metastatic hepatocellular carcinoma: a randomized, open-label, parallel-controlled phase Ⅱ–Ⅲ trial. J Clin Oncol, 2021, 39(27): 3002-3011.
41. Liu J, Xia S, Zhang B, et al. Small molecule tyrosine kinase inhibitors approved for systemic therapy of advanced hepatocellular carcinoma: recent advances and future perspectives. Discov Oncol, 2024, 15(1): 259. doi: 10.1007/s12672-024-01110-0.
42. Keam SJ, Duggan S. Donafenib: first approval. Drugs, 2021, 81(16): 1915-1920.
43. Boige V, Malka D, Bourredjem A, et al. Efficacy, safety, and biomarkers of single-agent bevacizumab therapy in patients with advanced hepatocellular carcinoma. Oncologist, 2012, 17(8): 1063-1072.
44. Sangro B, Gomez-Martin C, de la Mata M, 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): 81-88.
45. El-Khoueiry AB, Sangro B, Yau T, 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.
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CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Current research landscape of targeted therapy and immunotherapy for intermediate to advanced hepatocellular carcinoma

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