[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-seo-352441-105":3,"detail-sidebar-cat-0-en-105":81,"doc-detail-352441-en":131},{"code":4,"msg":5,"data":6},0,"ok",{"site_id":7,"language":8,"slug":9,"title":10,"keywords":11,"description":12,"schema_data":13,"social_meta":74,"head_meta":76,"extra_data":78,"updated_unix":80},105,"en","targeting-the-anxa2-cd63-exosomal-pd-l1-axis-in-hepatocellular-carcinoma-a-novel-mechanism-of-immune-evasion-and-its-implications-for-precision-immunotherapy","Targeting the ANXA2-CD63-exosomal PD-L1 axis in hepatocellular carcinoma - A novel mechanism of immune evasion and its implications for precision immunotherapy","","Background and Purpose: Hepatocellular carcinoma (HCC) drives global cancer mortality through late detection and resistance, including limited effectiveness of immune checkpoint blockade (ICB). Tumor-derived exosomal PD-L1 suppresses T-cell function by engaging PD-1, inducing exhaustion and systemic immunosuppression. This study tested whether Annexin A2 (ANXA2) regulates exosomal PD-L1 in HCC to promote immune escape. Results: ANXA2 increased in HCC and linked to fewer CD8+ T cells and poor survival. ANXA2 knockout reduced exosome secretion and exosomal PD-L1, impairing suppression of CD8+ activation. ANXA2 loss slowed tumor growth in immunocompetent mice and reduced CD63 stability, implicating lysosome-associated turnover. Conclusions: ANXA2 enhances immune evasion via CD63-stabilized exosomal PD-L1, supporting a novel target to improve ICB efficacy.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/healthcare/","Healthcare",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/targeting-the-anxa2-cd63-exosomal-pd-l1-axis-in-hepatocellular-carcinoma-a-novel-mechanism-of-immune-evasion-and-its-implications-for-precision-immunotherapy/352441/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/targeting-the-anxa2-cd63-exosomal-pd-l1-axis-in-hepatocellular-carcinoma-a-novel-mechanism-of-immune-evasion-and-its-implications-for-precision-immunotherapy/352441.png","ImageObject",300,407,{"name":42,"@type":43},"Levi","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-10-27","2026-09-22",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",12,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"How does ANXA2 affect exosomal PD-L1 in hepatocellular carcinoma?","Question",{"text":63,"@type":64},"ANXA2 modulates exosomal PD-L1 expression by maintaining CD63 protein stability, which supports PD-L1 incorporation into exosomes. ANXA2 knockout reduces exosome secretion and exosomal PD-L1 levels.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"What experimental evidence links ANXA2 to immune evasion?",{"text":68,"@type":64},"Bioinformatic analyses associate ANXA2 upregulation with fewer CD8+ T cells and poor survival. Functional assays show control exosomes suppress CD8+ T-cell activation, whereas exosomes from ANXA2 knockout cells do not.",{"name":70,"@type":61,"acceptedAnswer":71},"Why is the study relevant to precision immunotherapy?",{"text":72,"@type":64},"Because ANXA2-driven, tumor-specific regulation of exosomal PD-L1 can contribute to ICB resistance. Targeting this pathway may enhance ICB efficacy and improve responses across exosome-dependent cancers.","https://schema.org",{"og:url":32,"og:type":75,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":77,"canonical":32},"index,follow",{"doc_id":79,"site_id":7},352441,1790126027,{"code":4,"msg":82,"data":83},"success",[84,88,92,96,101,106,110,115,120,123,127],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":85,"show_sort_weight":86,"slug":87},"Story & Novel",90,"story-novel",{"id":26,"doc_module":4,"doc_module_name":25,"category_name":89,"show_sort_weight":90,"slug":91},"Literature",80,"literature",{"id":33,"doc_module":4,"doc_module_name":25,"category_name":93,"show_sort_weight":94,"slug":95},"Exam",70,"exam",{"id":97,"doc_module":4,"doc_module_name":25,"category_name":98,"show_sort_weight":99,"slug":100},5,"Comic",60,"comic",{"id":102,"doc_module":4,"doc_module_name":25,"category_name":103,"show_sort_weight":104,"slug":105},6,"Technology",50,"technology",{"id":107,"doc_module":4,"doc_module_name":25,"category_name":29,"show_sort_weight":108,"slug":109},7,40,"healthcare",{"id":111,"doc_module":4,"doc_module_name":25,"category_name":112,"show_sort_weight":113,"slug":114},8,"Research & Report",30,"research-report",{"id":116,"doc_module":4,"doc_module_name":25,"category_name":117,"show_sort_weight":118,"slug":119},9,"Religion & Spirituality",20,"religion-spirituality",{"id":118,"doc_module":4,"doc_module_name":25,"category_name":121,"show_sort_weight":118,"slug":122},"World Cup","world-cup",{"id":124,"doc_module":4,"doc_module_name":25,"category_name":125,"show_sort_weight":124,"slug":126},10,"Lifestyle","lifestyle",{"id":128,"doc_module":4,"doc_module_name":25,"category_name":129,"show_sort_weight":97,"slug":130},19,"General","general",{"code":4,"msg":82,"data":132},{"doc_id":79,"user_id":133,"nickname":42,"user_avatar":134,"doc_module":4,"category_id":107,"category_name":29,"doc_title":10,"doc_description":12,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":55,"is_deleted":4,"is_public":22,"is_downloadable":22,"audit_status":22,"page_count":140,"language":141,"language_code":8,"site_id":7,"html_lang":8,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":12,"update_tm":145,"read_time":146},7971461740909,"https://ap-avatar.wpscdn.com/davatar_155a257f0dc6eb9ab79c44ca47cae57d","Neoplasia 73 (2026) 101280  \nContents lists available at ScienceDirect  \nNeoplasia  \njournal [homepage:](homepage: www.elsevier.com/locate/neo)[ www.elsevier.com/locate/neo](homepage: www.elsevier.com/locate/neo)  \n| Targeting the ANXA2-CD63-exosomal PD-L1 axis in hepatocellular   carcinoma: A novel mechanism of immune evasion and its implications for precision immunotherapy\u003Cbr>Jian Zhang a,1, Ying Gu b,1, Fangchao Zhao c,d, Yong Chene, Yuqing Xia e, Dekang Gaof, Qiang Yuan a,*, Xuming Baia,*\u003Cbr>a Department of Interventional Radiology, The Second Affiliated Hospital of Soochow University, No.1055, Sanxiang Rd, Suzhou 215004, China b Department of Clinical Nutrition, The Second Affiliated Hospital of Soochow University, No. 1055, Sanxiang Rd, Suzhou 215004, China c Department of Thoracic Surgery, The Second Hospital of Hebei Medical University, No. 215 Heping West Rd, Shijiazhuang 050000, China d Department of Thoracic Surgery, The First Affiliated Hospital of Soochow University, No. 899, Ping Hai Rd, Suzhou 215006, China e Department of Gastroenterology, The Second Affiliated Hospital of Soochow University, No.1055, Sanxiang Rd, Suzhou 215004, China f Department of General Surgery, The Second Affiliated Hospital of Soochow University, No. 1055, Sanxiang Rd, Suzhou 215004, China |  |  |\n| --- | --- | --- |\n| A R T I C L E I N F O |  | A B S T R A C T |\n| Keywords:\u003Cbr>Hepatocellular carcinoma Exosomal PD-L1 Annexin A2\u003Cbr>Immune evasion T-cell suppression |  | Background and Purpose: Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related deaths globally due to late diagnosis and resistance to therapies, including immune checkpoint blockade (ICB). Tumor-derived exosomes carrying programmed death-ligand 1 (PD-L1) have emerged as key mediators of immune evasion by binding PD-1 on T cells, thereby inducing T cell exhaustion and systemic immunosuppression. This study investigated whether Annexin A2 (ANXA2) modulates exosomal PD-L1 expression in HCC cells to inhibit T-cell function and promote immune escape.\u003Cbr>Results: Bioinformatic analyses (TIMER2.0, TCGA) showed ANXA2 upregulation in HCC, correlating with fewer CD8⁺ T cells and poor survival. ANXA2 knockout (KO) in Hepa1-6 cells reduced exosome secretion and exosomal PD-L1, confirmed by EM, nanoparticle tracking, and WB. Exosomes from controls suppressed CD8⁺ T cell activation (reducing CD69, IL-2, IFN-γ, TNF-α), while KO exosomes did not. ANXA2 KO tumors grew slower in immunocompetent C57BL/6 J mice but not in immunodeficient BALB/c Nude mice, highlighting immune dependence. ANXA2 depletion reduced CD63 protein stability without affecting mRNA. CD63 re-expression in KO cells restored exosomal PD-L1, indicating ANXA2 maintains CD63 stability for PD-L1 exosomal incorporation. Transcriptomic and pharmacologic evidence further supported a role for lysosome-associated turnover in CD63 loss upon ANXA2 depletion.\u003Cbr>Conclusions: ANXA2 drives HCC immune evasion by upregulating exosomal PD-L1 via CD63 stabilization, offering a novel target to enhance ICB efficacy. This work highlights a tumor-specific exosome regulation mechanism, with potential implications for immunotherapy across exosome-dependent cancers. |\n\nIntroduction  \nHepatocellular carcinoma (HCC), a leading cause of cancer-related mortality globally, is characterized by late-stage diagnosis and therapeutic resistance, which contribute to its dismal prognosis [1]. While immune checkpoint blockade (ICB) targeting the PD-1/PD-L1 axis has provided clinical benefits for advanced HCC patients, objective response  \nrates remain below 20%, with most patients developing resistance due to immune evasion mechanisms [2,3]. The immunosuppressive tumor microenvironment (TME) is a central determinant ofICB resistance, and exosomes—30–150 nm lipid bilayer vesicles released via multivesicular body (MVB)-plasma membrane fusion—have emerged as critical mediators of intercellular communication, capable of remodeling the","cbCainWNzVOx1AqN","https://ap.wps.com/l/cbCainWNzVOx1AqN","pdf",13878830,13,"English","# Introduction\n## Tumor microenvironment and exosomal PD-L1\n## Need for identifying regulators of exosomal PD-L1 sorting\n## Role of Annexin A2 in tumor progression and resistance","[{\"question\":\"How does ANXA2 affect exosomal PD-L1 in hepatocellular carcinoma?\",\"answer\":\"ANXA2 modulates exosomal PD-L1 expression by maintaining CD63 protein stability, which supports PD-L1 incorporation into exosomes. ANXA2 knockout reduces exosome secretion and exosomal PD-L1 levels.\"},{\"question\":\"What experimental evidence links ANXA2 to immune evasion?\",\"answer\":\"Bioinformatic analyses associate ANXA2 upregulation with fewer CD8+ T cells and poor survival. Functional assays show control exosomes suppress CD8+ T-cell activation, whereas exosomes from ANXA2 knockout cells do not.\"},{\"question\":\"Why is the study relevant to precision immunotherapy?\",\"answer\":\"Because ANXA2-driven, tumor-specific regulation of exosomal PD-L1 can contribute to ICB resistance. Targeting this pathway may enhance ICB efficacy and improve responses across exosome-dependent cancers.\"}]","Targeting the ANXA2-CD63-exosomal PD-L1 axis in hepatocellular carcinoma - A novel mechanism of immune evasion and its implications for precision immunotherapy | PDF",1790099644,33]