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Our group developed Delta One T (DOT) cells, an allogeneic V\u03b41-enriched \u03b3\u03b4 T-cell product with demonstrated efficacy in CRC models, but the critical mechanisms guiding their tumor homing are unclear. Here we show that DOT cells acquire a specific chemokine receptor profile during expansion to support tumor infiltration, characterized by prominent CXCR3 expression. Importantly, CXCR3 ligands (CXCL9\u201311) are expressed by CRC cell lines and primary tumors, and correlate with V\u03b41 T cell infiltration and DOT-cell recruitment. CXCR3 signaling is critical for DOT-cell migration in vitro and in vivo, as pharmacologic blockade reduced tumor homing, whereas enhancing CXCR3 ligand expression increased DOT-cell infiltration and improved tumor control. These findings establish CXCR3 signaling as a key regulator of DOT-cell trafficking and a prime target to boost \u03b3\u03b4 T cell-based immunotherapies for CRC.<\/jats:p>","DOI":"10.1136\/jitc-2025-014668","type":"journal-article","created":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T13:50:13Z","timestamp":1779976213000},"page":"e014668","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["CXCR3 signaling promotes Delta One T cell recruitment and antitumor efficacy in colorectal cancer"],"prefix":"10.1136","volume":"14","clinical-trial-number":[{"clinical-trial-number":"nct04777994","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Mariana","family":"Carreira","sequence":"first","affiliation":[{"name":"GIMM, Lisbon, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leandro","family":"Barros","sequence":"additional","affiliation":[{"name":"GIMM, Lisbon, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael M","family":"Cruz","sequence":"additional","affiliation":[{"name":"Hospital de Santa Maria, Lisbon, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Hospital de Santa Maria, Lisbon, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Costa","sequence":"additional","affiliation":[{"name":"Hospital de Santa Maria, Lisbon, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos M","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Hospital de Santa Maria, Lisbon, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofia","family":"Mensurado","sequence":"additional","affiliation":[{"name":"GIMM, Lisbon, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4141-9302","authenticated-orcid":false,"given":"Bruno","family":"Silva-Santos","sequence":"additional","affiliation":[{"name":"Universidade de Lisboa, Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2448-8699","authenticated-orcid":false,"given":"Rafael","family":"Blanco-Dom\u00ednguez","sequence":"additional","affiliation":[{"name":"GIMM, Lisbon, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2026,5,28]]},"reference":[{"key":"2026052807150950000_14.5.e014668.1","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1146\/annurev-immunol-083024-024653","article-title":"\u03b3\u03b4 T Cells for Cancer Immunotherapy: Unconventional Players Take the Spotlight","volume":"44","author":"Stevens","year":"2026","journal-title":"Annu Rev Immunol"},{"key":"2026052807150950000_14.5.e014668.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.gastha.2023.09.007"},{"key":"2026052807150950000_14.5.e014668.3","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1038\/s41586-022-05593-1","article-title":"\u03b3\u03b4 T cells are effectors of immunotherapy in cancers with HLA class I defects","volume":"613","author":"de Vries","year":"2023","journal-title":"Nature New Biol"},{"key":"2026052807150950000_14.5.e014668.4","doi-asserted-by":"crossref","DOI":"10.1080\/2162402X.2017.1347742","article-title":"Distinctive features of tumor-infiltrating \u03b3\u03b4 T lymphocytes in human colorectal cancer","volume":"6","author":"Meraviglia","year":"2017","journal-title":"Oncoimmunology"},{"key":"2026052807150950000_14.5.e014668.5","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-16-0597"},{"key":"2026052807150950000_14.5.e014668.6","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1038\/s43018-025-00948-9","article-title":"Dual modulation of cytotoxic and checkpoint receptors tunes the efficacy of adoptive Delta One T cell therapy against colorectal cancer","volume":"6","author":"Blanco-Dom\u00ednguez","year":"2025","journal-title":"Nat Cancer"},{"key":"2026052807150950000_14.5.e014668.7","doi-asserted-by":"crossref","unstructured":"Wang X , Zhang Y , Wang S , et al . 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