信迪利单抗联合贝伐珠单抗在晚期肝细胞癌中的应用现状与耐药机制

刘玲珑; 刘延

doi:10.12449/JCH260729

信迪利单抗联合贝伐珠单抗在晚期肝细胞癌中的应用现状与耐药机制

DOI: 10.12449/JCH260729

刘玲珑¹,
刘延^2, , ,

1.
遵义医科大学第二临床学院，贵州遵义 563000
2.
贵州省人民医院肝胆外科，贵阳 550002

基金项目:

贵州省人民医院科研基金 (GZSYBS2022203)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：刘玲珑负责设计论文框架，起草论文，拟定写作思路，指导撰写文章并最后定稿；刘延负责论文修改。

详细信息

通信作者:
刘延， 2422560337@qq.com （ORCID： 0009-0007-4439-4864）

计量
- 文章访问数: 5
- HTML全文浏览量: 0
- PDF下载量: 1
- 被引次数: 0
出版历程
- 收稿日期: 2025-11-24
- 录用日期: 2025-12-26
- 出版日期: 2026-07-25

Current application and resistance mechanisms of sintilimab combined with bevacizumab in advanced hepatocellular carcinoma

Linglong Liu¹,
Yan Liu^{2
, ,
,}

1.
The Second Clinical College of Zunyi Medical University，Zunyi，Guizhou 563000，China
2.
Department of Hepatobiliary Surgery，Guizhou Provincial People’s Hospital，Guiyang 550002，China

Research funding:

Scientific Research Fund Project of Guizhou Provincial People’s Hospital (GZSYBS2022203)

More Information

Corresponding author: Liu Yan， 2422560337@qq.com （ORCID： 0009-0007-4439-4864）

摘要

摘要: 肝细胞癌（HCC）在全球范围内疾病负担沉重，其发生与免疫抑制性肿瘤微环境密切相关。晚期HCC的系统治疗已进入免疫联合治疗时代，ORIENT-32研究奠定了信迪利单抗联合贝伐珠单抗方案的一线地位，其临床价值后续也被多项真实世界研究验证。耐药性是该方案及其他多种靶免联合方案应用时面临的重要挑战。当前研究重点正转向解析其临床表型与分子机制，并推动生物标志物从静态预测向动态监测的临床转化。未来，克服耐药、优化联合策略及实现精准个体化治疗，是提升患者生存获益的关键。本综述旨在系统评估信迪利单抗联合贝伐珠单抗方案在真实世界中的疗效与安全性，初步探讨其耐药机制，并综述预测疗效及指导克服耐药的关键生物标志物研究进展，为优化晚期HCC的精准治疗策略提供依据。
- 癌，肝细胞 /
- 信迪利单抗 /
- 贝伐珠单抗 /
- 抗药性，肿瘤 /
- 生物标记，肿瘤
Abstract: Hepatocellular carcinoma （HCC） imposes a significant global disease burden， and the development of HCC is closely associated with an immunosuppressive tumor microenvironment. Systemic therapy for advanced HCC has entered the era of immune combination therapy. The ORIENT-32 study has established the regimen of sintilimab combined with bevacizumab as the first-line therapy， and multiple real-world studies have confirmed its clinical value. Overcoming drug resistance remains a major challenge during the application of various combination regimens of targeted therapy and immunotherapy， including this particular regimen. Current research focus is gradually shifting toward deciphering its clinical phenotypes and molecular mechanisms， while promoting the clinical translation of biomarkers from static prediction to dynamic monitoring. In the future， overcoming drug resistance， optimizing combination strategies， and achieving precise individualized treatment are key to enhancing the survival benefit of patients. This article systematically evaluates the efficacy and safety of the sintilimab+bevacizumab regimen in a real-world setting， preliminarily discusses its drug resistance mechanism， and reviews the research advances in the biomarkers for predicting treatment response and guiding drug resistance overcoming， in order to provide a basis for optimizing the precise treatment strategies for advanced HCC.
- Carcinoma， Hepatocellular /
- Sintilimab /
- Bevacizumab /
- Drug Resistance， Neoplasm /
- Biomarkers， Tumor

HTML全文

参考文献(55)

[1]	Hepatocellular carcinoma[J]. Nat Rev Dis Primers, 2021, 7: 7. DOI: 10.1038/s41572-021-00245-6.
[2]	Rumgay H, Ferlay J, de Martel C, et al. Global, regional and national burden of primary liver cancer by subtype[J]. Eur J Cancer, 2022, 161: 108- 118. DOI: 10.1016/j.ejca.2021.11.023.
[3]	Chidambaranathan-Reghupaty S, Fisher P B, Sarkar D. Hepatocellular carcinoma(HCC): Epidemiology, etiology and molecular classification[J]. Adv Cancer Res, 2021, 149: 1- 61. DOI: 10.1016/bs.acr.2020.10.001.
[4]	Omata M, Cheng A L, Kokudo N, et al. Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: A 2017 update[J]. Hepatol Int, 2017, 11( 4): 317- 370. DOI: 10.1007/s12072-017-9799-9.
[5]	Wolf E, Rich N E, Marrero J A, et al. Use of hepatocellular carcinoma surveillance in patients with cirrhosis: A systematic review and meta-analysis[J]. Hepatology, 2021, 73( 2): 713- 725. DOI: 10.1002/hep.31309.
[6]	Shan T H, Ran X H, Li H Z, et al. Disparities in stage at diagnosis for liver cancer in China[J]. J Natl Cancer Cent, 2023, 3( 1): 7- 13. DOI: 10.1016/j.jncc.2022.12.002.
[7]	Chen F, Li Q H, Xu X M, et al. Clinical characteristics and risk factors of hepatitis B virus-related cirrhosis/hepatocellular carcinoma: A single-center retrospective study[J]. Liver Res, 2023, 7( 3): 237- 243. DOI: 10.1016/j.livres.2023.07.004.
[8]	Franssen B, Alshebeeb K, Tabrizian P, et al. Differences in surgical outcomes between hepatitis B- and hepatitis C-related hepatocellular carcinoma: A retrospective analysis of a single North American center[J]. Ann Surg, 2014, 260( 4): 650- 656. DOI: 10.1097/SLA.0000000000000917.
[9]	Llovet J M, Willoughby C E, Singal A G, et al. Nonalcoholic steatohepatitis-related hepatocellular carcinoma: Pathogenesis and treatment[J]. Nat Rev Gastroenterol Hepatol, 2023, 20( 8): 487- 503. DOI: 10.1038/s41575-023-00754-7.
[10]	Lodato F, Mazzella G, Festi D, et al. Hepatocellular carcinoma prevention: A worldwide emergence between the opulence of developed countries and the economic constraints of developing nations[J]. World J Gastroenterol, 2006, 12( 45): 7239- 7249. DOI: 10.3748/wjg.v12.i45.7239.
[11]	Bertot L C, Adams L A. Trends in hepatocellular carcinoma due to non-alcoholic fatty liver disease[J]. Expert Rev Gastroenterol Hepatol, 2019, 13( 2): 179- 187. DOI: 10.1080/17474124.2019.1549989.
[12]	Singal A G, Kanwal F, Llovet J M. Global trends in hepatocellular carcinoma epidemiology: Implications for screening, prevention and therapy[J]. Nat Rev Clin Oncol, 2023, 20( 12): 864- 884. DOI: 10.1038/s41571-023-00825-3.
[13]	Llovet J M, Zucman-Rossi J, Pikarsky E, et al. Hepatocellular carcinoma[J]. Nat Rev Dis Primers, 2016, 2: 16018. DOI: 10.1038/nrdp.2016.18.
[14]	Dunn G P, Old L J, Schreiber R D. The three Es of cancer immunoediting[J]. Annu Rev Immunol, 2004, 22: 329- 360. DOI: 10.1146/annurev.immunol.22.012703.104803.
[15]	Knudsen E S, Gopal P, Singal A G. The changing landscape of hepatocellular carcinoma etiology, genetics, and therapy[J]. Am J Pathol, 2014, 184( 3): 574- 583. DOI: 10.1016/j.ajpath.2013.10.028.
[16]	Hoshida Y. Hepatocellular Carcinoma: Translational Precision Medicine Approaches[M]. Cham: Humana Press, 2019.
[17]	Ringelhan M, Pfister D, O’Connor T, et al. The immunology of hepatocellular carcinoma[J]. Nat Immunol, 2018, 19( 3): 222- 232. DOI: 10.1038/s41590-018-0044-z.
[18]	Flecken T, Schmidt N, Hild S, et al. Immunodominance and functional alterations of tumor-associated antigen-specific CD8⁺ T-cell responses in hepatocellular carcinoma[J]. Hepatology, 2014, 59( 4): 1415- 1426. DOI: 10.1002/hep.26731.
[19]	Street S E, Hayakawa Y, Zhan Y F, et al. Innate immune surveillance of spontaneous B cell lymphomas by natural killer cells and gammadelta T cells[J]. J Exp Med, 2004, 199( 6): 879- 884. DOI: 10.1084/jem.20031981.
[20]	Keirsse J, van Damme H, Geeraerts X, et al. The role of hepatic macrophages in liver metastasis[J]. Cell Immunol, 2018, 330: 202- 215. DOI: 10.1016/j.cellimm.2018.03.010.
[21]	Chen V L, Oliveri A, Miller M J, et al. PNPLA3 genotype and diabetes identify patients with nonalcoholic fatty liver disease at high risk of incident cirrhosis[J]. Gastroenterology, 2023, 164( 6): 966- 977.e17. DOI: 10.1053/j.gastro.2023.01.040.
[22]	Hu Y F, He W Z, Huang Y P, et al. Fatty acid synthase-suppressor screening identifies sorting nexin 8 as a therapeutic target for NAFLD[J]. Hepatology, 2021, 74( 5): 2508- 2525. DOI: 10.1002/hep.32045.
[23]	Han Y M, Chen Z B, Yang Y, et al. Human CD14⁺CTLA-4⁺ regulatory dendritic cells suppress T-cell response by cytotoxic T-lymphocyte antigen-4-dependent IL-10 and indoleamine-2, 3-dioxygenase production in hepatocellular carcinoma[J]. Hepatology, 2014, 59( 2): 567- 579. DOI: 10.1002/hep.26694.
[24]	Hoechst B, Ormandy L A, Ballmaier M, et al. A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4⁺CD25⁺Foxp3⁺ T cells[J]. Gastroenterology, 2008, 135( 1): 234- 243. DOI: 10.1053/j.gastro.2008.03.020.
[25]	Finkin S, Yuan D T, Stein I, et al. Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma[J]. Nat Immunol, 2015, 16( 12): 1235- 1244. DOI: 10.1038/ni.3290.
[26]	Llovet J M, Castet F, Heikenwalder M, et al. Immunotherapies for hepatocellular carcinoma[J]. Nat Rev Clin Oncol, 2022, 19( 3): 151- 172. DOI: 10.1038/s41571-021-00573-2.
[27]	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[J]. Cancer Discov, 2019, 9( 8): 1124- 1141. DOI: 10.1158/2159-8290.CD-19-0074.
[28]	Xu Y C, Poggio M, Jin H Y, et al. Translation control of the immune checkpoint in cancer and its therapeutic targeting[J]. Nat Med, 2019, 25( 2): 301- 311. DOI: 10.1038/s41591-018-0321-2.
[29]	Sun H C, Tang Z Y. Angiogenesis in hepatocellular carcinoma: The retrospectives and perspectives[J]. J Cancer Res Clin Oncol, 2004, 130( 6): 307- 319. DOI: 10.1007/s00432-003-0530-y.
[30]	Shen Y C, Hsu C, Cheng A L. Molecular targeted therapy for advanced hepatocellular carcinoma: Current status and future perspectives[J]. J Gastroenterol, 2010, 45( 8): 794- 807. DOI: 10.1007/s00535-010-0270-0.
[31]	Topalian S L, Hodi F S, Brahmer J R, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer[J]. N Engl J Med, 2012, 366( 26): 2443- 2454. DOI: 10.1056/NEJMoa1200690.
[32]	Sha Ying, Yu Ke, Jia Jiajia, et al. Research advances of immune checkpoint inhibitors for neoadjuvant therapy in locally advanced gastric cancer[J]. Chin J Dig Surg, 2025, 24( 9): 1214- 1220. DOI: 10.3760/cma.j.cn115610-20250827-00559. 沙颖, 余柯, 贾佳佳, 等. 免疫检查点抑制剂在局部进展期胃癌新辅助治疗中的研究进展[J]. 中华消化外科杂志, 2025, 24( 9): 1214- 1220. DOI: 10.3760/cma.j.cn115610-20250827-00559..
[33]	Hepato-Pancreato-Biliary MDT Professional Committee of Chinese Chapter of International Hepato-Pancreato-Biliary Association; Group of Liver Surgery, Chinese Society of Surgery; General Surgery Subcommittee, Chinese Geriatrics Society, et al. Expert consensus on multidisciplinary collaboration in perioperative immunotherapy for hepatocellular carcinoma(2025 edition)[J]. Chin J Dig Surg, 2025, 24( 6): 678- 689. DOI: 10.3760/cma.j.cn115610-20250609-00278. 国际肝胆胰协会中国分会肝胆胰MDT专业委员会, 中华医学会外科学分会肝脏外科学组, 中国老年医学学会普外科分会, 等. 肝细胞癌围手术期免疫治疗多学科协作专家共识(2025版)[J]. 中华消化外科杂志, 2025, 24( 6): 678- 689. DOI: 10.3760/cma.j.cn115610-20250609-00278.
[34]	Kurebayashi Y, Matsuda K, Ueno A, et al. Immunovascular classification of HCC reflects reciprocal interaction between immune and angiogenic tumor microenvironments[J]. Hepatology, 2022, 75( 5): 1139- 1153. DOI: 10.1002/hep.32201.
[35]	Yau T, Galle P R, 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[J]. Lancet, 2025, 405( 10492): 1851- 1864. DOI: 10.1016/S0140-6736(25)00403-9.
[36]	Finn R S, Qin S K, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma[J]. N Engl J Med, 2020, 382( 20): 1894- 1905. DOI: 10.1056/NEJMoa1915745.
[37]	Zarlashat Y, Mushtaq H, Pham L, et al. Advancements in immunotherapeutic treatments for hepatocellular carcinoma: Potential of combination therapies[J]. Int J Mol Sci, 2024, 25( 13): 6830. DOI: 10.3390/ijms25136830.
[38]	Pinato D J, Murray S M, Forner A, et al. Trans-arterial chemoembolization as a loco-regional inducer of immunogenic cell death in hepatocellular carcinoma: Implications for immunotherapy[J]. J Immunother Cancer, 2021, 9( 9): e003311. DOI: 10.1136/jitc-2021-003311.
[39]	Llovet J M, Villanueva A, Marrero J A, et al. Trial design and endpoints in hepatocellular carcinoma: AASLD consensus conference[J]. Hepatology, 2021, 73( Suppl 1): 158- 191. DOI: 10.1002/hep.31327.
[40]	Ren Z G, Xu J M, Bai Y X, et al. Sintilimab plus a bevacizumab biosimilar(IBI₃05) versus sorafenib in unresectable hepatocellular carcinoma(ORIENT-32): A randomised, open-label, phase 2-3 study[J]. Lancet Oncol, 2021, 22( 7): 977- 990. DOI: 10.1016/S1470-2045(21)00252-7.
[41]	Liu W F, Quan B, Lu S X, et al. First-line systemic treatment strategies for unresectable hepatocellular carcinoma: A systematic review and network meta-analysis of randomized clinical trials[J]. Front Oncol, 2021, 11: 771045. DOI: 10.3389/fonc.2021.771045.
[42]	Sherman R E, Anderson S A, Dal Pan G J, et al. Real-world evidence- what is it and what can it tell us?[J]. N Engl J Med, 2016, 375( 23): 2293- 2297. DOI: 10.1056/NEJMsb1609216.
[43]	Berger M L, Sox H, Willke R J, et al. Good practices for real-world data studies of treatment and/or comparative effectiveness: Recommendations from the joint ISPOR-ISPE Special Task Force on real-world evidence in health care decision making[J]. Pharmacoepidemiol Drug Saf, 2017, 26( 9): 1033- 1039. DOI: 10.1002/pds.4297.
[44]	Goh M J, Oh J H, Park Y, et al. Efficacy and safety of lenvatinib therapy for unresectable hepatocellular carcinoma in a real-world practice in Korea[J]. Liver Cancer, 2021, 10( 1): 52- 62. DOI: 10.1159/000512239.
[45]	Su Zhan, Che Jinhui, Pei Ruifeng. Real-world study of sintilimab combined with bevacizumab in patients with advanced hepatocellular carcinoma[J]. China Pharm, 2024, 27( 3): 485- 490. DOI: 10.12173/j.issn.1008-049X.202402057. 苏展, 车金辉, 裴锐锋. 信迪利单抗联合贝伐珠单抗对晚期肝细胞癌的真实世界研究[J]. 中国药师, 2024, 27( 3): 485- 490. DOI: 10.12173/j.issn.1008-049X.202402057.
[46]	Zhang Y X, Miao Y H, Sun W, et al. Sintilimab plus a bevacizumab biosimilar(IBI₃05) in advanced HCC with Child-Pugh A/B liver function: A real-world multicenter retrospective study[J]. Front Oncol, 2025, 15: 1681663. DOI: 10.3389/fonc.2025.1681663.
[47]	Zeng X H, Jia Y X, Chen H M, et al. A real-world analysis of survival and cost-effectiveness of sintilimab plus bevacizumab biosimilar regimen in patients with advanced hepatocellular carcinoma[J]. J Cancer Res Clin Oncol, 2023, 149( 11): 9213- 9219. DOI: 10.1007/s00432-023-04775-2.
[48]	Zou Tiantian, Qin Wei, Zhu Ying, et al. Immune microenvironment and immunotherapy in hepatocellular carcinoma: Research progress and development directions[J]. Chin J Gen Surg, 2020, 29( 7): 785- 797. DOI: 10.7659/j.issn.1005-6947.2020.07.002. 邹添添, 覃伟, 朱迎, 等. 肝癌免疫微环境与免疫治疗: 研究进展与发展趋势[J]. 中国普通外科杂志, 2020, 29( 7): 785- 797. DOI: 10.7659/j.issn.1005-6947.2020.07.002.
[49]	Deng Na, Li Xiaomi, Ding Xiaoyan, et al. Current status and progress of second-line treatment for hepatocellular carcinoma[J/CD]. Chin J Liver Dis Electron Version, 2024, 16( 1): 1- 6. DOI: 10.3969/j.issn.1674-7380.2024.01.001. 邓娜, 栗晓咪, 丁晓燕, 等. 肝细胞癌二线治疗的现状和进展[J/CD]. 中国肝脏病杂志(电子版), 2024, 16( 1): 1- 6. DOI: 10.3969/j.issn.1674-7380.2024.01.001.
[50]	Ladd A D, Duarte S, Sahin I, et al. Mechanisms of drug resistance in HCC[J]. Hepatology, 2024, 79( 4): 926- 940. DOI: 10.1097/hep.0000000000000237.
[51]	Zhang Tianqi, Cao Yuzhe, Zuo Mengxuan, et al. Research advances in second-line therapies for hepatocellular carcinoma after resistance to targeted therapy combined with immunotherapy[J]. J Clin Hepatol, 2024, 40( 2): 386- 390. DOI: 10.12449/JCH240227. 张天奇, 曹钰哲, 左孟轩, 等. 肝癌靶向联合免疫治疗耐药后的二线治疗方案研究进展[J]. 临床肝胆病杂志, 2024, 40( 2): 386- 390. DOI: 10.12449/JCH240227.
[52]	Zhu A X, Abbas A R, de Galarreta M R, et al. Molecular correlates of clinical response and resistance to atezolizumab in combination with bevacizumab in advanced hepatocellular carcinoma[J]. Nat Med, 2022, 28( 8): 1599- 1611. DOI: 10.1038/s41591-022-01868-2.
[53]	Vellanki P J, Ghosh S, Pathak A, et al. Regulatory implications of ctDNA in immuno-oncology for solid tumors[J]. J Immunother Cancer, 2023, 11( 2): e005344. DOI: 10.1136/jitc-2022-005344.
[54]	Saltarella I, Morabito F, Giuliani N, et al. Prognostic or predictive value of circulating cytokines and angiogenic factors for initial treatment of multiple myeloma in the GIMEMA MM0305 randomized controlled trial[J]. J Hematol Oncol, 2019, 12( 1): 4. DOI: 10.1186/s13045-018-0691-4.
[55]	Cambier S, Gouwy M, Proost P. The chemokines CXCL8 and CXCL12: Molecular and functional properties, role in disease and efforts towards pharmacological intervention[J]. Cell Mol Immunol, 2023, 20( 3): 217- 251. DOI: 10.1038/s41423-023-00974-6.