{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T19:13:45Z","timestamp":1782587625622,"version":"3.54.5"},"reference-count":85,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T00:00:00Z","timestamp":1774310400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Colorectal cancer (CRC) remains a significant global health concern. Improving the efficacy of immunotherapy, particularly for microsatellite-stable tumors, requires a better understanding of the unconventional T-cell populations that regulate intestinal immunity. \u03b3\u03b4 T cells are uniquely positioned at the epithelial barrier and function as rapid sentinels, recognizing stress signals independently of classical antigen presentation. In a healthy colon, \u03b3\u03b4 intraepithelial lymphocytes (IELs) and lamina propria lymphocytes (LPLs) form separate compartments influenced by tissue-specific butyrophilin-like (BTNL) interactions, microbiota-derived signals, and cytokine environments. These signals imprint divergent effector programs, ranging from IFN-\u03b3-producing, cytotoxic responses to IL-17-driven tissue repair and inflammation. In CRC, however, these subsets exhibit remarkable plasticity. In mouse models, for example, V\u03b31\n                    <jats:sup>+<\/jats:sup>\n                    and V\u03b37\n                    <jats:sup>+<\/jats:sup>\n                    IELs mediate potent antitumor immunity, whereas V\u03b34\n                    <jats:sup>+<\/jats:sup>\n                    and V\u03b36\n                    <jats:sup>+<\/jats:sup>\n                    LPLs can acquire IL-17-dependent pro-tumor functions. In contrast, human data depict a different balance. Across multiple cohorts, tumor-infiltrating \u03b3\u03b4 T cells, predominantly the V\u03b41\n                    <jats:sup>+<\/jats:sup>\n                    and V\u03b42\n                    <jats:sup>+<\/jats:sup>\n                    subsets, exhibit robust cytotoxic and IFN-\u03b3-associated phenotypes. Meanwhile, the existence of bona fide IL-17-producing \u03b3\u03b4 T cells remains highly controversial. Higher \u03b3\u03b4 T-cell abundance correlates with better outcomes, even in tumors with defective HLA class I expression, where \u03b3\u03b4 T cells can mediate the therapeutic effects of PD-1 blockade. Emerging findings reveal subset heterogeneity, context-dependent functional states, and a crucial role for NK-receptor-mediated recognition, particularly via NKG2D. Together, these insights position \u03b3\u03b4 T cells as pivotal yet understudied regulators of CRC progression and immunotherapy responsiveness. Understanding their subset-specific biology could lead to next-generation \u03b3\u03b4-based therapies tailored to the unique immunogenic constraints of colorectal cancer.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1761668","type":"journal-article","created":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T16:00:54Z","timestamp":1774368054000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Functional heterogeneity of \u03b3\u03b4 T cells in colorectal cancer"],"prefix":"10.3389","volume":"17","author":[{"given":"Andr\u00e9 Miguel","family":"Vaz-Pinto","sequence":"first","affiliation":[{"name":"Institute of Systems Immunology, Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf","place":["Hamburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Immo","family":"Prinz","sequence":"additional","affiliation":[{"name":"Institute of Systems Immunology, Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf","place":["Hamburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J Clin"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2022.06.008","article-title":"Nivolumab plus low-dose ipilimumab in previously treated patients with microsatellite instability-high\/mismatch repair-deficient metastatic colorectal cancer: 4-year follow-up from CheckMate 142","volume":"33","author":"Andr\u00e9","year":"2022","journal-title":"Ann Oncol Off J Eur Soc Med Oncol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2017699","article-title":"Pembrolizumab in microsatellite-instability\u2013high advanced colorectal cancer","volume":"383","author":"Andr\u00e9","year":"2020","journal-title":"N Engl J Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-019-0126-x","article-title":"Immunotherapy in colorectal cancer: rationale, challenges and potential","volume":"16","author":"Ganesh","year":"2019","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14184453","article-title":"The evolving landscape of immunotherapy in locally advanced rectal cancer patients","volume":"14","author":"Germani","year":"2022","journal-title":"Cancers"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-3083.1995.tb03541.x","article-title":"Regional specialization of intraepithelial T cells in the murine small and large intestine","volume":"41","author":"Boll","year":"1995","journal-title":"Scand J Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/7.9.1473","article-title":"Intra-epithelial lymphocytes. 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