[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-seo-349428-105":3,"detail-sidebar-cat-0-en-105":81,"doc-detail-349428-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","tumor-draining-lymph-nodes-shape-the-tumor-microenvironment-through-enrichment-of-tumor-reactive-effector-exhausted-cd8-t-cells","Tumor-draining lymph nodes shape the tumor microenvironment through enrichment of tumor-reactive effector-exhausted CD8 + T cells","","Tumor-draining lymph nodes act as central hubs in the cancer-immunity cycle, shaping how T cells are primed, exhausted, and ultimately contribute to tumor control. This study compares tumor-draining lymph nodes and tumor microenvironments between colorectal cancer subtypes with microsatellite instability and microsatellite stability using integrative multi-omics analysis. A distinct CD8+ T cell population showing terminal exhaustion but retaining anti-tumor activity is identified, with lineage tracing implicating tumor-draining lymph nodes. The microenvironment is supported by IL21+ CD4+ T cells, CXCL10+ myeloid cells, and microsatellite instability tumor cell activation of cGAS-STING signaling.",{"@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/tumor-draining-lymph-nodes-shape-the-tumor-microenvironment-through-enrichment-of-tumor-reactive-effector-exhausted-cd8-t-cells/349428/",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/tumor-draining-lymph-nodes-shape-the-tumor-microenvironment-through-enrichment-of-tumor-reactive-effector-exhausted-cd8-t-cells/349428.png","ImageObject",300,407,{"name":42,"@type":43},"Bulrr","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-10-30","2026-09-22",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",14,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"What is the central role of tumor-draining lymph nodes in anti-tumor immunity?","Question",{"text":63,"@type":64},"They are critical sites for antigen presentation and T cell priming and help orchestrate responses during the cancer-immunity cycle. They can also serve as reservoirs for CD8+ T cells and pre-exhausted T cells that are important for immune checkpoint blockade efficacy.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"How do microsatellite instability and microsatellite-stable colorectal cancers differ in immune response?",{"text":68,"@type":64},"They show substantially different tumor biology, prognosis, and sensitivity to immune checkpoint blockade. MSI tumors are described as highly sensitive to ICB, while most MSS tumors remain resistant.",{"name":70,"@type":61,"acceptedAnswer":71},"What does the study identify as a key mediator in MSI colorectal cancer?",{"text":72,"@type":64},"A distinct population of CD8+ T cells with terminal exhaustion that still retains strong anti-tumor activity. These cells are tumor-reactive, associated with tertiary lymphoid structure formation, and enriched in MSI colorectal 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},349428,1790138521,{"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":128,"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},5909892115043,"https://ap-avatar.wpscdn.com/davatar_6f874abed73319feea01a86fa6f0fab8","Signal Transduction [and Targeted Therapy](and Targeted Therapy www.nature.com/sigtrans)[ www.nature.com/sigtrans](and Targeted Therapy www.nature.com/sigtrans)  \nARTICLE OPEN  \nTumor-draining lymph nodes shape the tumor microenvironment through enrichment of tumor-reactive effector-exhausted CD8 + T cells  \nDeyang Kong1,2, Lin Feng2,3, Yu Sun1,2, Huiru Zhang1,2, Jialiang Fan2,3, Yueyi An4,5, Yunlong Wu1,2, Yuelu Zhu6, Qi Zhang 1,2, Renshen Xiang1,2, Shuaibing Lu1,2, Wenjing Yang1,2, Wei Pei 1, Zheng Wang1, Shengdian Wang4,5 ✉, Jianqing Xu7 ✉ and Haizeng Zhang 1,2 ✉  \n\n|  |  |  |\n| --- | --- | --- |\n|  | Tumor-draining lymph nodes are central to anti-tumor immunity and influence the response to immunotherapy. Colorectal cancers with microsatellite instability and microsatellite stability differ substantially in tumor biology, prognosis and sensitivity to immune checkpoint blockade. However, the differences in tumor-draining lymph nodes between these two subtypes and their contribution to distinct anti-tumor immune responses remain poorly understood. Here, we performed an integrative multi-omics analysis to systematically compare tumor-draining lymph nodes and tumor microenvironments in these two colorectal cancer subtypes. Weidentified a distinct population of CD8+ T cells that displayed terminal exhaustion while retaining strong anti-tumor activity. These cells were highly tumor reactive, associated with tertiary lymphoid structure formation and enriched in microsatellite instability colorectal cancers. Lineage tracing indicated that they originated in tumor-draining lymph nodes. In microsatellite instability colorectal cancers, tumor-draining lymph nodes contained more pre-exhausted T cells, dendritic cells with enhanced antigenpresenting capacity and fewer regulatory T cells, thereby providing both precursors and a supportive niche for the development of these effector-exhausted T cells. Meanwhile, within tumors, IL21+CD4+ T cells and CXCL10+ myeloid cells promoted the differentiation and recruitment of these cells through cytokine signaling and increased major histocompatibility complex expression. Colorectal cancer cells with microsatellite instability further reinforced this immune ecosystem by activating the cyclic GMP-AMP synthase–stimulator of interferon genes pathway. Collectively, our findings identify effector-exhausted CD8+ T cells as key mediators of favorable immunity in microsatellite instability colorectal cancers and highlight the pivotal role of tumor-draining |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  | lymph nodes in shaping the tumor immune landscape. |  |\n|  |  |  |\n|  |  |  |\n|  | Signal Transduction and Targeted Therapy (2026)11:273 ; [https://doi.org/10.1038/s41392-026-02858-3](https://doi.org/10.1038/s41392-026-02858-3) |  |\n|  |  |  |\n\nINTRODUCTION  \nLymph nodes are critical sites for antigen presentation and T cell priming and serve as central hubs in the cancer-immunity cycle.1 Increasing evidence highlights the pivotal role of tumor-draining lymph nodes (TdLNs) in orchestrating anti-tumor immunity and modulating responses to immunotherapy. TdLNs can function as reservoirs for CD8+ T cells, where initially primed cells can traffic to the tumor microenvironment (TME) for further activation and expansion into effector-like cytotoxic T cells.2,3 CD4+ T cells in TdLNs also exert key immunoregulatory functions that influenceanti-tumor responses through multiple mechanisms.4,5 Critically, pre-exhausted T cells (Tpex) residing in TdLNs have been identified as key mediators of immune checkpoint blockade (ICB) efficacy.2,3 Upon ICB treatment, these T cells are activated  \nand expanded within TdLNs and subsequently migrate into the tumor, where they exert anti-tumor effects.6,7 This process is often accompanied by clonal replacement, whereby intratumoral T cells are supplanted by clonal","cbCaiqC76HALAlDp","https://ap.wps.com/l/cbCaiqC76HALAlDp","pdf",9242669,"English","# Introduction\n## Background on tumor-draining lymph nodes and immune checkpoint blockade\n## Microsatellite instability versus microsatellite-stable colorectal cancer\n# Main findings\n## Integrative multi-omics comparison of tumor-draining lymph nodes and tumor microenvironments\n## Effector-exhausted CD8+ T cells associated with tertiary lymphoid structure formation\n## Supportive niche mechanisms involving CD4+ T cells, myeloid cells, and cGAS-STING signaling","[{\"question\":\"What is the central role of tumor-draining lymph nodes in anti-tumor immunity?\",\"answer\":\"They are critical sites for antigen presentation and T cell priming and help orchestrate responses during the cancer-immunity cycle. They can also serve as reservoirs for CD8+ T cells and pre-exhausted T cells that are important for immune checkpoint blockade efficacy.\"},{\"question\":\"How do microsatellite instability and microsatellite-stable colorectal cancers differ in immune response?\",\"answer\":\"They show substantially different tumor biology, prognosis, and sensitivity to immune checkpoint blockade. MSI tumors are described as highly sensitive to ICB, while most MSS tumors remain resistant.\"},{\"question\":\"What does the study identify as a key mediator in MSI colorectal cancer?\",\"answer\":\"A distinct population of CD8+ T cells with terminal exhaustion that still retains strong anti-tumor activity. These cells are tumor-reactive, associated with tertiary lymphoid structure formation, and enriched in MSI colorectal cancers.\"}]","Tumor-draining lymph nodes shape the tumor microenvironment through enrichment of tumor-reactive effector-exhausted CD8 + T cells | PDF",1790083284,48]