[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-352552-105":59,"doc-detail-352552-en":130},{"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":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":123,"head_meta":125,"extra_data":127,"updated_unix":129},105,"en","agr2-promotes-tumor-progression-by-regulating-macrophage-polarization-via-the-cd98hc-xctp-erk-pathway","AGR2 promotes tumor progression by regulating macrophage polarization via the CD98hc-xCT/p-ERK pathway","","Anterior gradient 2 (AGR2) contributes to tumor development, but its role in the tumor microenvironment and macrophage polarization remained unclear. This study evaluated AGR2 as a prognostic factor using pan-cancer TCGA analyses, assessed macrophage infiltration in clinical specimens, and tested recombinant AGR2 to determine polarization effects. AGR2 enhanced M2 polarization, promoted tumor cell proliferation and motility, activated the CD98hc-xCT/ERK pathway, and accelerated tumor growth in vivo while suppressing T-cell function.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/agr2-promotes-tumor-progression-by-regulating-macrophage-polarization-via-the-cd98hc-xctp-erk-pathway/352552/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/agr2-promotes-tumor-progression-by-regulating-macrophage-polarization-via-the-cd98hc-xctp-erk-pathway/352552.png","ImageObject",300,407,{"name":92,"@type":93},"Ophelia","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-27","2026-09-22",true,{"@type":102,"interactionType":103,"userInteractionCount":39},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"How was AGR2 evaluated as a prognostic factor in this study?","Question",{"text":112,"@type":113},"AGR2 expression and survival associations were analyzed using TCGA across pan-cancer datasets. Elevated AGR2 was linked to poor prognosis in multiple cancers.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What effect does recombinant AGR2 (rAGR2) have on macrophage polarization?",{"text":117,"@type":113},"rAGR2 promoted M2 polarization while inhibiting M1 polarization in macrophages. It also increased the pro-tumorigenic effects of M2-conditioned medium on cancer cell motility and proliferation.",{"name":119,"@type":110,"acceptedAnswer":120},"What is the proposed mechanism connecting AGR2 to tumor progression?",{"text":121,"@type":113},"AGR2 binds the CD98hc-xCT receptor complex and activates the ERK pathway. CD98hc knockdown abolished this ERK-dependent effect, supporting the pathway as a causal link.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},352552,1790806240,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":39,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},7971461741311,"https://ap-avatar.wpscdn.com/avatar/74000253aff267980c6?x-image-process=image/resize,m_fixed,w_180,h_180&k=1779345379180704826","TYPE Original Research PUBLISHED 26 February 2026 DOI 10.3389/fimmu.2026.1774238  \nOPEN ACCESS  \nEDITED BY  \nGaurisankar Sa,  \nBose Institute, India  \nREVIEWED BY  \nJing Lian,  \nShanxi Province Cancer Hospital, China Weihong Niu,  \nZhengzhou University, China  \n*CORRESPONDENCE  \nShan Jiang  \n [Shanjiang@whu.edu.cn](Shanjiang@whu.edu.cn)[ ](Shanjiang@whu.edu.cn)Liang Zhao  \n [liangzhao1992@whu.edu.cn](liangzhao1992@whu.edu.cn)  \n†These authors have contributed equally to this work  \nRECEIVED 23 December 2025  \nREVISED 06 February 2026  \nACCEPTED 16 February 2026  \nPUBLISHED 26 February 2026  \nCITATION  \nWu N, Zhao L and Jiang S (2026) AGR2 promotes tumor progression by regulating macrophage polarization via the CD98hc-xCT/p-ERK pathway. Front. Immunol. 17:1774238 .  \ndoi: 10.3389/fimmu.2026.1774238  \nCOPYRIGHT  \n© 2026 Wu, Zhao and Jiang. This is an 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.  \nAGR2 promotes tumor progression by regulating macrophage polarization via the CD98hc-xCT/p-ERK pathway  \nNaming Wu, Liang Zhao*† and Shan Jiang*†  \nDepartment of Dermatology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China  \nIntroduction: Anterior gradient 2 (AGR2) contributes to tumorigenesis, yet its function within the tumor microenvironment (TME) and in macrophage polarization remains unclear. This study assessed the prognostic significance of AGR2 and investigated its mechanism in cancer progression.  \nMethods: We used TCGA for pan-cancer AGR2 expression and survival analysis, examined macrophage infiltration in clinical specimens, and performed in vitro experiments with recombinant AGR2 (rAGR2) to assess macrophage polarization. We verified AGR2’s interaction with the CD98hc-xCT receptor complex and explored related mechanisms via CD98hc knockdown. In vivo experiments were conducted in B16-F10 melanoma and Lewis lung carcinoma (LLC) models using flow cytometry.  \nResults: Pan−cancer analyses showed that elevated AGR2 expression correlates with poor prognosis in multiple cancers and is associated with reduced immune infiltration. AGR2 is predominantly expressed in CD163+ M2−like tumor −associated macrophages (TAMs), with levels rising alongside tumor stage. In vitro, rAGR2 promoted M2 polarization while inhibiting M1 polarization of macrophages, and enhanced the pro−tumorigenic effects of M2−conditioned medium on cancer cell motility and proliferation. Mechanistically, AGR2 binds to the CD98hc−xCT receptor complex, activating the ERK pathway, an effect abrogated by CD98hc knockdown. In vivo, rAGR2 accelerated tumor growth in melanoma and lung cancer models, accompanied by increased TAM accumulation, a shift toward M2 polarization, and suppressed T-cell function. Discussion: AGR2 drives tumor progression by reprogramming TAMs toward an M2 phenotype and attenuating T−cell function via the CD98hc−xCT/p-ERK pathway, highlighting its potential as both a prognostic marker and a therapeutic target.  \nKEYWORDS  \nAGR2, CD98hc−xCT, macrophage polarization, p−ERK/ERK pathway, tumor microenvironment  \n1 Introduction  \nCancer progression is a complex multistep process orchestrated by both tumor cells and the surrounding tumor microenvironment (TME) (1, 2) . The TME, consisting of stromal cells, immune cells, and extracellular matrix components, plays a pivotal role in regulating tumor growth, invasion, metastasis, and therapeutic response (3, 4) . Among the diverse  \nFrontiers in Immunology 01 [frontiersin.org](frontiersin.org)  \nimmune cells in the TME, tumor-associated macrophages (TAMs) are the most abundant population, exhibiting high plasticity that","cbCaieMWutJh4sCY","https://ap.wps.com/l/cbCaieMWutJh4sCY","pdf",8480758,15,"English","# Introduction\n## Tumor microenvironment and TAM polarization\n## Anterior gradient 2 (AGR2) in cancer\n# Methods\n## TCGA analysis and survival correlations\n## Macrophage infiltration and polarization assays\n## CD98hc-xCT interaction and ERK pathway testing\n## In vivo tumor models and flow cytometry\n# Results\n## Pan-cancer prognostic value of AGR2\n## AGR2 expression in TAM subsets and tumor stage\n## Effects of rAGR2 on M1/M2 polarization\n## Mechanistic link to CD98hc-xCT and ERK activation\n## In vivo effects on tumor growth and immune function\n# Discussion\n## AGR2-mediated reprogramming of TAMs and immune attenuation","[{\"question\":\"How was AGR2 evaluated as a prognostic factor in this study?\",\"answer\":\"AGR2 expression and survival associations were analyzed using TCGA across pan-cancer datasets. Elevated AGR2 was linked to poor prognosis in multiple cancers.\"},{\"question\":\"What effect does recombinant AGR2 (rAGR2) have on macrophage polarization?\",\"answer\":\"rAGR2 promoted M2 polarization while inhibiting M1 polarization in macrophages. It also increased the pro-tumorigenic effects of M2-conditioned medium on cancer cell motility and proliferation.\"},{\"question\":\"What is the proposed mechanism connecting AGR2 to tumor progression?\",\"answer\":\"AGR2 binds the CD98hc-xCT receptor complex and activates the ERK pathway. CD98hc knockdown abolished this ERK-dependent effect, supporting the pathway as a causal link.\"}]","AGR2 promotes tumor progression by regulating macrophage polarization via the CD98hc-xCT/p-ERK pathway | PDF",1790100236,38]