[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-detail-410081-en":59,"doc-seo-410081-105":81},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":5,"data":60},{"doc_id":61,"user_id":62,"nickname":63,"user_avatar":64,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":66,"doc_content":67,"file_id":68,"file_url":69,"file_type":70,"file_size":71,"view_count":14,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":72,"language":73,"language_code":74,"site_id":75,"html_lang":74,"table_of_contents":76,"faqs":77,"seo_title":78,"seo_description":66,"update_tm":79,"read_time":80},410081,1099514068365,"Aurelia","https://ap-avatar.wpscdn.com/avatar/10000253d8d9f28188e?_k=1776742907772140068","New insights into combined immunotherapy for hepatocellular carcinoma associated with liver cirrhosis","Liver cirrhosis underlies most hepatocellular carcinoma (HCC) cases, creating a chronically inflamed, fibrotic, and immunosuppressed hepatic microenvironment that limits the effectiveness of immune-checkpoint inhibitors. This review summarizes recent theories and mechanisms explaining how cirrhosis reshapes the hepatic immune microenvironment to impair immunotherapy response. It details changes in dendritic cells, T cells, macrophages, and neutrophils, and outlines potential intervention targets and combination strategies supported by basic and translational research.","TYPE Review  \nPUBLISHED 18 December 2025 DOI 10.3389/fimmu.2025.1741398  \nOPEN ACCESS  \nEDITED BY  \nYan Yan,  \nMayo Clinic Florida, United States  \nREVIEWED BY  \nBo Hu,  \nFudan University, China Chunyan Yu,  \nBeihua University, China  \n*CORRESPONDENCE  \nJiyao Sheng  \n [shengjy15@mails.jlu.edu.cn](shengjy15@mails.jlu.edu.cn)  \n†These authors share first authorship  \nRECEIVED 07 November 2025  \nREVISED 02 December 2025  \nACCEPTED 08 December 2025  \nPUBLISHED 18 December 2025  \nCITATION  \nLiu Y, Cong K, Li Q, Zhang D and Sheng J (2025) New insights into combined immunotherapy for hepatocellular carcinoma associated with liver cirrhosis.  \nFront. Immunol. 16:1741398 .  \ndoi: 10.3389/fimmu.2025.1741398  \nCOPYRIGHT  \n© 2025 Liu, Cong, Li, Zhang and Sheng. This isan open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.  \nNew insights into combined immunotherapy for hepatocellular carcinoma associated with liver cirrhosis  \nYufan Liu 1†, Kexin Cong 2†, Qiao Li 1, Dan Zhang 1 and Jiyao Sheng 1*  \n1 Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun, Jilin, China, 2 Department of Surgery, The Second Hospital of Jilin University, Changchun, Jilin, China  \nWorldwide, most (80%–90%) hepatocellular carcinomas (HCCs) develop against a background of liver cirrhosis, where chronic inflammation, fibrosis, and immune dysfunction collectively shape an immunosuppressive hepatic microenvironment. Despite significant breakthroughs in HCC treatment with immune-checkpoint inhibitors, objective response rates remain limited inpatients with advanced HCC, primarily because of cirrhosis-mediated remodeling of the hepatic immune microenvironment. This review systematically summarizes recent theories and mechanisms by which cirrhosis impairs immuno therapy through reshaping the hepatic immune microenvironment. It also covers alterations in the quantity, function, and metabolism of dendritic cells, T cells, macrophages, and neutrophils. Furthermore, it proposes potential intervention targets and combination therapy strategies aimed at correcting these immune abnormalities, all of which have demonstrated value in basic and translational research. In summary, cirrhosis constitutes the pathogenic foundation of HCC and represents a critical determinant of immunotherapy response. The future integration of immunotherapeutic strategies targeting the cirrhotic immune microenvironment holds promise as a key direction for enhancing immunotherapy efficacy in cirrhosis-associated HCC.  \nKEYWORDS  \ncombined immunotherapy, hepatocellular carcinoma, immune microenvironment, immunotherapy, liver cirrhosis  \n1 Introduction  \nLiver cancer ranks second among causes of cancer mortality worldwide, with roughly 866,000 new diagnoses each year (1) . Hepatocellular carcinoma (HCC) is the predominant histologic type, comprising approximately 90% of primary hepatic malignancies (2) . In contrast to many other common solid cancers driven primarily by stochastic, multifactorial  \nFrontiers in Immunology 01 [frontiersin.org](frontiersin.org)  \nmutational events, HCC typically emerges through a stepwise cascade of persistent hepatic injury, followed by inflammation,fibrogenesis, and ultimately cirrhosis (3) . Globally, 80%–90% HCCs arise in cirrhotic livers (4, 5) .  \nThe core pathological features of liver cirrhosis include diffuse fibrosis, the formation of regenerative nodules, and significant intraliver vascular remodeling. Persistent chronic injury irreversibly alters normal lobular architecture, producing an interlaced pattern of hepatocellular parenchyma and fib","cbCaim39uyvlKYZ8","https://ap.wps.com/l/cbCaim39uyvlKYZ8","pdf",1066722,17,"English","en",105,"# Introduction\n## Cirrhosis-linked development of HCC\n## Immune microenvironment alterations\n# Immunotherapy and rationale for combinations\n## Limitations of immune-checkpoint inhibitor monotherapy\n# Immune-cell targets in cirrhosis-associated HCC\n## Dendritic cells, T cells, macrophages, neutrophils\n# Potential intervention strategies\n## Future directions for improving immunotherapy efficacy","[{\"question\":\"Why is liver cirrhosis important for hepatocellular carcinoma immunotherapy response?\",\"answer\":\"Most HCCs arise in cirrhotic livers, where chronic inflammation, fibrosis, and immune dysfunction form an immunosuppressive microenvironment that reduces immunotherapy effectiveness.\"},{\"question\":\"How does this review describe cirrhosis-related effects on immune cells?\",\"answer\":\"It summarizes how cirrhosis alters the quantity, function, and metabolism of dendritic cells, T cells, macrophages, and neutrophils, including shifts toward impaired or exhausted immune phenotypes.\"},{\"question\":\"What limitation of immune-checkpoint inhibitor (ICI) therapy is highlighted?\",\"answer\":\"Across pivotal studies, ICI monotherapy shows objective response rates around 15%–20% in advanced HCC, motivating combined strategies targeting the cirrhotic immune microenvironment.\"}]","New insights into combined immunotherapy for hepatocellular carcinoma associated with liver cirrhosis | PDF",1790584219,43,{"code":4,"msg":82,"data":83},"ok",{"site_id":75,"language":74,"slug":84,"title":65,"keywords":85,"description":66,"schema_data":86,"social_meta":140,"head_meta":142,"extra_data":144,"updated_unix":145},"new-insights-into-combined-immunotherapy-for-hepatocellular-carcinoma-associated-with-liver-cirrhosis","",{"@graph":87,"@context":139},[88,102,122],{"@type":89,"itemListElement":90},"BreadcrumbList",[91,95,97,100],{"item":92,"name":93,"@type":94,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":96,"name":9,"@type":94,"position":14},"https://docshare.wps.com/document/",{"item":98,"name":40,"@type":94,"position":99},"https://docshare.wps.com/document/research-report/",3,{"item":101,"name":65,"@type":94,"position":19},"https://docshare.wps.com/document/new-insights-into-combined-immunotherapy-for-hepatocellular-carcinoma-associated-with-liver-cirrhosis/410081/",{"url":101,"name":65,"@type":103,"image":104,"author":109,"headline":65,"publisher":111,"fileFormat":114,"inLanguage":74,"description":66,"dateModified":115,"datePublished":116,"encodingFormat":114,"isAccessibleForFree":117,"interactionStatistic":118},"DigitalDocument",{"url":105,"@type":106,"width":107,"height":108},"https://docshare.wps.com/thumbnails/new-insights-into-combined-immunotherapy-for-hepatocellular-carcinoma-associated-with-liver-cirrhosis/410081.png","ImageObject",300,407,{"name":63,"@type":110},"Person",{"url":92,"name":112,"@type":113},"DocShare","Organization","application/pdf","2026-09-29","2026-09-28",true,{"@type":119,"interactionType":120,"userInteractionCount":14},"InteractionCounter",{"@type":121},"ViewAction",{"@type":123,"mainEntity":124},"FAQPage",[125,131,135],{"name":126,"@type":127,"acceptedAnswer":128},"Why is liver cirrhosis important for hepatocellular carcinoma immunotherapy response?","Question",{"text":129,"@type":130},"Most HCCs arise in cirrhotic livers, where chronic inflammation, fibrosis, and immune dysfunction form an immunosuppressive microenvironment that reduces immunotherapy effectiveness.","Answer",{"name":132,"@type":127,"acceptedAnswer":133},"How does this review describe cirrhosis-related effects on immune cells?",{"text":134,"@type":130},"It summarizes how cirrhosis alters the quantity, function, and metabolism of dendritic cells, T cells, macrophages, and neutrophils, including shifts toward impaired or exhausted immune phenotypes.",{"name":136,"@type":127,"acceptedAnswer":137},"What limitation of immune-checkpoint inhibitor (ICI) therapy is highlighted?",{"text":138,"@type":130},"Across pivotal studies, ICI monotherapy shows objective response rates around 15%–20% in advanced HCC, motivating combined strategies targeting the cirrhotic immune microenvironment.","https://schema.org",{"og:url":101,"og:type":141,"og:title":65,"og:site_name":112,"og:description":66},"article",{"robots":143,"canonical":101},"index,follow",{"doc_id":61,"site_id":75},1790672551]