[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-seo-352284-105":3,"detail-sidebar-cat-0-en-105":80,"doc-detail-352284-en":130},{"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":73,"head_meta":75,"extra_data":77,"updated_unix":79},105,"en","iron-fueled-ferroptosis-a-new-axis-for-immunomodulation-to-overcome-cancer-drug-resistance-from-immune-microenvironment-crosstalk-to-therapeutic-translation","Iron-fueled ferroptosis - a new axis for immunomodulation to overcome cancer drug resistance - from immune microenvironment crosstalk to therapeutic translation","","Resistance to chemotherapy and targeted therapy in cancer often arises from apoptosis evasion, whereas ferroptosis—iron-dependent regulated cell death driven by lipid peroxidation—provides a promising alternative. The tumor immune microenvironment governs ferroptosis susceptibility through signaling from CD8+ T cells and other immune populations such as Tregs, MDSCs, and macrophages. Inducing ferroptosis promotes immunogenic cell death, boosts T-cell infiltration, and can synergize with immune checkpoint blockade. This review covers molecular sensitivity, immune-ferroptosis crosstalk, combination approaches, and barriers to clinical translation including toxicity and patient stratification.",{"@graph":14,"@context":72},[15,34,55],{"@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/research-report/","Research & Report",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/iron-fueled-ferroptosis-a-new-axis-for-immunomodulation-to-overcome-cancer-drug-resistance-from-immune-microenvironment-crosstalk-to-therapeutic-translation/352284/",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/iron-fueled-ferroptosis-a-new-axis-for-immunomodulation-to-overcome-cancer-drug-resistance-from-immune-microenvironment-crosstalk-to-therapeutic-translation/352284.png","ImageObject",300,407,{"name":42,"@type":43},"Lucas Martin","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-09-25","2026-09-22",true,{"@type":52,"interactionType":53,"userInteractionCount":30},"InteractionCounter",{"@type":54},"ViewAction",{"@type":56,"mainEntity":57},"FAQPage",[58,64,68],{"name":59,"@type":60,"acceptedAnswer":61},"Why does cancer drug resistance limit chemotherapy and targeted therapy effectiveness?","Question",{"text":62,"@type":63},"Cancer cells often develop resistance by evading therapy-induced death signals, including apoptosis evasion through anti-apoptotic proteins or mutations in apoptosis-related genes.","Answer",{"name":65,"@type":60,"acceptedAnswer":66},"What biological mechanism makes ferroptosis relevant to overcoming drug resistance?",{"text":67,"@type":63},"Ferroptosis is iron-dependent and triggered by lipid peroxidation accumulation, and resistant cancers may show metabolic and antioxidant defects that create selective vulnerability.",{"name":69,"@type":60,"acceptedAnswer":70},"How does the tumor immune microenvironment influence ferroptosis susceptibility?",{"text":71,"@type":63},"Immune cells modulate ferroptosis via cytokine and redox signaling; for example, CD8+ T cell-derived IFN-γ can downregulate system Xc- and upregulate ACSL4, while other immune populations further tune ferroptosis.","https://schema.org",{"og:url":32,"og:type":74,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":76,"canonical":32},"index,follow",{"doc_id":78,"site_id":7},352284,1790193477,{"code":4,"msg":81,"data":82},"success",[83,87,91,95,100,105,110,114,119,122,126],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":84,"show_sort_weight":85,"slug":86},"Story & Novel",90,"story-novel",{"id":26,"doc_module":4,"doc_module_name":25,"category_name":88,"show_sort_weight":89,"slug":90},"Literature",80,"literature",{"id":33,"doc_module":4,"doc_module_name":25,"category_name":92,"show_sort_weight":93,"slug":94},"Exam",70,"exam",{"id":96,"doc_module":4,"doc_module_name":25,"category_name":97,"show_sort_weight":98,"slug":99},5,"Comic",60,"comic",{"id":101,"doc_module":4,"doc_module_name":25,"category_name":102,"show_sort_weight":103,"slug":104},6,"Technology",50,"technology",{"id":106,"doc_module":4,"doc_module_name":25,"category_name":107,"show_sort_weight":108,"slug":109},7,"Healthcare",40,"healthcare",{"id":111,"doc_module":4,"doc_module_name":25,"category_name":29,"show_sort_weight":112,"slug":113},8,30,"research-report",{"id":115,"doc_module":4,"doc_module_name":25,"category_name":116,"show_sort_weight":117,"slug":118},9,"Religion & Spirituality",20,"religion-spirituality",{"id":117,"doc_module":4,"doc_module_name":25,"category_name":120,"show_sort_weight":117,"slug":121},"World Cup","world-cup",{"id":123,"doc_module":4,"doc_module_name":25,"category_name":124,"show_sort_weight":123,"slug":125},10,"Lifestyle","lifestyle",{"id":127,"doc_module":4,"doc_module_name":25,"category_name":128,"show_sort_weight":96,"slug":129},19,"General","general",{"code":4,"msg":81,"data":131},{"doc_id":78,"user_id":132,"nickname":42,"user_avatar":133,"doc_module":4,"category_id":111,"category_name":29,"doc_title":10,"doc_description":12,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":30,"is_deleted":4,"is_public":22,"is_downloadable":22,"audit_status":22,"page_count":139,"language":140,"language_code":8,"site_id":7,"html_lang":8,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":12,"update_tm":144,"read_time":145},8796095360427,"https://ap-avatar.wpscdn.com/davatar_994ba38a5ba835b3df7d355c54d3ed8d","TYPE Review  \nPUBLISHED 13 January 2026  \nDOI 10.3389/fimmu.2025.1726210  \nOPEN ACCESS  \nEDITED BY  \nTitto Augustine,  \nPurdue University Indianapolis, United States  \nREVIEWED BY  \nRan Tao,  \nTexas A&M University Baylor College of Dentistry, United States  \nFangmin Zhong, Nanchang University, China Tengfei Liu,  \nShanghai Jiao Tong University, China Hailiang Wang,  \nQingdao University, China Fuwen Yao,  \nStanford University, United States Afrasim Moin,  \nUniversity of Hail, Saudi Arabia Xiao Wei,  \nChengdu University, China  \n*CORRESPONDENCE  \nRuipei Chen  \n [329082694@qq.com](329082694@qq.com)[ ](329082694@qq.com)Hongpeng Chen  \n [380260714@qq.com](380260714@qq.com)[ ](380260714@qq.com)Junbing He  \n[junbingg@gdmu.edu.cn](junbingg@gdmu.edu.cn)  \n†These authors have contributed equally to this work  \nRECEIVED 16 October 2025  \nREVISED 02 November 2025  \nACCEPTED 22 December 2025  \nPUBLISHED 13 January 2026  \nCITATION  \nWu Y, Zhang K, Jiang N, Chen Z, Sun X, Zha H, Lin M, Li J, Pan X,  \nChen J, He J, Chen H and Chen R (2026) Iron-fueled ferroptosis: a new axis for immunomodulation to overcome cancer drug resistance—from immune microenvironment crosstalk to therapeutic translation.  \nFront. Immunol. 16:1726210 .  \ndoi: 10.3389/fimmu.2025.1726210  \nCOPYRIGHT  \n© 2026 Wu, Zhang, Jiang, Chen, Sun, Zha, Lin, Li, Pan, Chen, He, Chen and Chen. 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.  \nIron-fueled ferroptosis: a new axis for immunomodulation to overcome cancer drug resistance—from immune microenvironment crosstalk to therapeutic translation  \nYimao Wu 1,2†, Kaiyu Zhang 3†, Naijun Jiang 4†, Zichang Chen 2†, Xiaojing Sun 5, Hongyu Zha 3, Mingjun Lin 3, Jingxin Li 3, Xiaocheng Pan 6, Jiadong Chen 6, Junbing He 7*,  \nHongpeng Chen 1* and Ruipei Chen 1*  \n1Oncology, Jieyang People’s Hospital, Jieyang, China, 2Second Clinical Medical College, Guangdong Medical University, Dongguan, China, 3Second Clinical Medical College, Anhui Medical University, HeFei, China, 4 First Clinical Medical College, Anhui Medical University, Hefei, China, 5 Fourth Clinical Medical College, Anhui Medical University, Hefei, China, 6Jieyang People’s Hospital, Jieyang, China, 7Jieyang Medical Research Center, Jieyang People’s Hospital, Jieyang, China  \nResistance to chemotherapy and targeted therapy in cancer is largely due to evasion of apoptosis, but ferroptosis—an iron-dependent form of regulated cell death driven by lipid peroxidation—offers a promising alternative, particularly in aggressive and therapy-resistant subtypes. The tumor immune microenvironment plays a central role in modulating ferroptosis susceptibility: CD8+ T cell-derived IFNg downregulates system Xc-and upregulates ACSL4, while other immune cells such as Tregs, MDSCs, and macrophages further fine-tune ferroptosis through cytokine and redox signaling. Importantly, ferroptosis induction promotes immunogenic cell death, enhancing T cell infiltration and synergizing with immune checkpoint blockade to achieve sustained antitumor immunity. This review delineates the molecular basis of ferroptosis sensitivity in resistant cancers, explores immune-ferroptosis crosstalk, evaluates combination strategies with immunotherapy, and discusses challenges such as toxicity and patient stratification to advance clinical translation.  \nKEYWORDS  \nferroptosis, cancer drug resistance, antitumor immunity, tumor microenvironment, immunotherapy, lipid peroxidation  \nFrontiers in Immunology 01 [frontiersin.org](frontiersin.org)  \n1 Introduction  \n1.1 Clinical background  \nIn cancer therapy, the development of drug resista","cbCaiskDAaT9Qv5G","https://ap.wps.com/l/cbCaiskDAaT9Qv5G","pdf",4873721,33,"English","# 1 Introduction\n## 1.1 Clinical background\n## 1.2 The unique significance of ferroptosis","[{\"question\":\"Why does cancer drug resistance limit chemotherapy and targeted therapy effectiveness?\",\"answer\":\"Cancer cells often develop resistance by evading therapy-induced death signals, including apoptosis evasion through anti-apoptotic proteins or mutations in apoptosis-related genes.\"},{\"question\":\"What biological mechanism makes ferroptosis relevant to overcoming drug resistance?\",\"answer\":\"Ferroptosis is iron-dependent and triggered by lipid peroxidation accumulation, and resistant cancers may show metabolic and antioxidant defects that create selective vulnerability.\"},{\"question\":\"How does the tumor immune microenvironment influence ferroptosis susceptibility?\",\"answer\":\"Immune cells modulate ferroptosis via cytokine and redox signaling; for example, CD8+ T cell-derived IFN-γ can downregulate system Xc- and upregulate ACSL4, while other immune populations further tune ferroptosis.\"}]","Iron-fueled ferroptosis - a new axis for immunomodulation to overcome cancer drug resistance - from immune microenvironment crosstalk to therapeutic translation | PDF",1790098752,83]