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Checkpoint inhibitor blockade has changed treatment in other cancers, yet in colorectal cancer it largely benefits only microsatellite instability-high or mismatch repair-deficient tumors. Most sporadic CRCs are microsatellite-stable and show low immune-cell infiltration, leading to no clinical benefit. Immunotherapy requires T cell presence in the tumor microenvironment, where T-cell subsets are heterogeneous and can be exhausted, dysfunctional, or checkpoint-high; this review discusses their roles and CAR-T potential.",{"@graph":69,"@context":123},[70,84,106],{"@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/t-cells-in-colorectal-cancer-unravelling-the-function-of-different-t-cell-subsets-in-the-tumor-microenvironment/378062/",{"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/t-cells-in-colorectal-cancer-unravelling-the-function-of-different-t-cell-subsets-in-the-tumor-microenvironment/378062.png","ImageObject",300,407,{"name":92,"@type":93},"Riley West","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-01","2026-09-24",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",12,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"Why does checkpoint inhibitor therapy work poorly in most colorectal cancer patients?","Question",{"text":113,"@type":114},"In most sporadic colorectal cancers, tumors are microsatellite-stable with low infiltration of immune cells, so checkpoint blockade has limited effect. Only MSI-H or dMMR tumors generally show meaningful benefit.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"What role do T cells play in the tumor microenvironment for immunotherapy?",{"text":118,"@type":114},"Checkpoint inhibitors require infiltrating T cells in the tumor microenvironment. T cells are key effector cells, and the immunoscore reflects their prognostic importance in colorectal cancer.",{"name":120,"@type":111,"acceptedAnswer":121},"How can the limitations of conventional CD8+ T cells be addressed?",{"text":122,"@type":114},"Even CD8+ T cells can become exhausted, hyporesponsive, or dysfunctional and express checkpoint molecules. Unconventional T cell subsets with a distinct T cell receptor can recognize antigens in an MHC-independent manner and may help bridge innate and adaptive immunity; the review also considers overcoming T cell exclusion in “cold” tumors and discusses CAR-T possibilities.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},378062,1790624799,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":140,"language":141,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":67,"update_tm":145,"read_time":146},1099523885074,"https://ap-avatar.wpscdn.com/davatar_9964176cb1d06d4a9deccf72a44ae3dc","Review  \nT Cells in Colorectal Cancer: Unravelling the Function of Different T Cell Subsets in the Tumor Microenvironment  \nZiwen Zheng 1, Thomas Wieder 2, Bernhard Mauerer 1,3,4, Luisa Schäfer 1, Rebecca Kesselring 1,3,4,† and Heidi Braumüller 1, *,†  \nCitation: Zheng, Z.; Wieder, T.; Mauerer, B.; Schäfer, L.; Kesselring, R.; Braumüller, H. T Cells in Colorectal Cancer: Unravelling the Function of Different T Cell Subsetsin the Tumor Microenvironment. Int.  \nJ. Mol. Sci. 2023, 24, 11673. [https://](https://)[ ](https://)[doi.org/10.3390/ijms241411673](doi.org/10.3390/ijms241411673)  \nAcademic Editor: Carmine Stolfi  \nReceived: 16 June 2023  \nRevised: 17 July 2023  \nAccepted: 18 July 2023  \nPublished: 19 July 2023  \nCopyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \n1 Department of General and Visceral Surgery, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; [ziwen.zheng@uniklinik-freiburg.de](ziwen.zheng@uniklinik-freiburg.de) (Z.Z.); [bernhard.mauerer@uniklinik-freiburg.de](bernhard.mauerer@uniklinik-freiburg.de) (B.M.); [luisa.schaefer@uniklinik-freiburg.de](luisa.schaefer@uniklinik-freiburg.de) (L.S.); [rebecca.kesselring@uniklinik-freiburg.de](rebecca.kesselring@uniklinik-freiburg.de) (R.K.)  \n2 Department of Vegetative and Clinical Physiology, Institute of Physiology, Eberhard Karls University Tübingen, 72074 Tübingen, Germany; thomas.wieder@uni-tuebingen.de  \n3 German Cancer Consortium (DKTK) Partner Site Freiburg, 79106 Freiburg, Germany  \n4 German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany  \n* Correspondence: heidi.braumueller@uniklinik-freiburg.de † These authors contributed equally to this work.  \nAbstract: Therapeutic options for metastatic colorectal cancer (mCRC) are very limited, and the prognosis using combination therapy with a chemotherapeutic drug and a targeted agent, e.g., epidermal growth factor receptor or tyrosine kinase, remains poor. Therefore, mCRC is associated with a poor median overall survival (mOS) of only 25–30 months. Current immunotherapies with checkpoint inhibitor blockade (ICB) have led to a substantial change in the treatment of several cancers, such as melanoma and non-small cell lung cancer. In CRC, ICB has only limited effects, except in patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) tumors, which comprise about 15% of sporadic CRC patients and about 4% of patients with metastatic CRC. The vast majority of sporadic CRCs are microsatellite-stable (MSS) tumors with low levels of infiltrating immune cells, in which immunotherapy has no clinical benefit so far. Immunotherapy with checkpoint inhibitors requires the presence of infiltrating T cells into the tumor microenvironment (TME) . This makes T cells the most important effector cells in the TME, as evidenced by the establishment of the immunoscore—a method to estimate the prognosis of CRC patients. The microenvironment of a tumor contains several types of T cells that are anti-tumorigenic, such as CD8+ T cells or protumorigenic, such as regulatory T cells (Tregs) or T helper 17 (Th17) cells. However, even CD8+ T cells show marked heterogeneity, e.g., they can become exhausted, enter a state of hyporesponsiveness or become dysfunctional and express high levels of checkpoint molecules, the targets for ICB. To kill cancer cells, CD8+ T cells need the recognition of the MHC class I, which is often downregulated on colorectal cancer cells. In this case, a population of unconventional T cells with a 􀀍􀀎 T cell receptor can overcome the limitations of the conventional CD8+ T cells with an 􀀋􀀌T cell receptor. 􀀍􀀎 T cells recognize antigens in an MHC-indep","cbCaia3IN1n1pUek","https://ap.wps.com/l/cbCaia3IN1n1pUek","pdf",2331550,35,"English","# Abstract\n# 1. Introduction\n## 1.1. Immune Cell Infiltration into the Consensus Molecular CRC Subtypes","[{\"question\":\"Why does checkpoint inhibitor therapy work poorly in most colorectal cancer patients?\",\"answer\":\"In most sporadic colorectal cancers, tumors are microsatellite-stable with low infiltration of immune cells, so checkpoint blockade has limited effect. Only MSI-H or dMMR tumors generally show meaningful benefit.\"},{\"question\":\"What role do T cells play in the tumor microenvironment for immunotherapy?\",\"answer\":\"Checkpoint inhibitors require infiltrating T cells in the tumor microenvironment. T cells are key effector cells, and the immunoscore reflects their prognostic importance in colorectal cancer.\"},{\"question\":\"How can the limitations of conventional CD8+ T cells be addressed?\",\"answer\":\"Even CD8+ T cells can become exhausted, hyporesponsive, or dysfunctional and express checkpoint molecules. Unconventional T cell subsets with a distinct T cell receptor can recognize antigens in an MHC-independent manner and may help bridge innate and adaptive immunity; the review also considers overcoming T cell exclusion in “cold” tumors and discusses CAR-T possibilities.\"}]","T Cells in Colorectal Cancer - Unravelling the Function of Different T Cell Subsets in the Tumor Microenvironment | PDF",1790228227,88]