{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T04:30:26Z","timestamp":1774413026621,"version":"3.50.1"},"reference-count":43,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2025,4,16]],"date-time":"2025-04-16T00:00:00Z","timestamp":1744761600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2025,4,16]],"date-time":"2025-04-16T00:00:00Z","timestamp":1744761600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Cancer"],"DOI":"10.1038\/s43018-025-00948-9","type":"journal-article","created":{"date-parts":[[2025,4,16]],"date-time":"2025-04-16T09:03:17Z","timestamp":1744794197000},"page":"1056-1072","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Dual modulation of cytotoxic and checkpoint receptors tunes the efficacy of adoptive Delta One T cell therapy against colorectal cancer"],"prefix":"10.1038","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2448-8699","authenticated-orcid":false,"given":"Rafael","family":"Blanco-Dom\u00ednguez","sequence":"first","affiliation":[]},{"given":"Leandro","family":"Barros","sequence":"additional","affiliation":[]},{"given":"Mariana","family":"Carreira","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7150-3068","authenticated-orcid":false,"given":"Manon","family":"van der Ploeg","sequence":"additional","affiliation":[]},{"given":"Carolina","family":"Conde\u00e7o","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9200-2454","authenticated-orcid":false,"given":"Gabriel","family":"Mars\u00e8res","sequence":"additional","affiliation":[]},{"given":"Cristina","family":"Ferreira","sequence":"additional","affiliation":[]},{"given":"Carla","family":"Costa","sequence":"additional","affiliation":[]},{"given":"Carlos M.","family":"Ferreira","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7521-9531","authenticated-orcid":false,"given":"Julie","family":"D\u00e9chanet-Merville","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6122-1024","authenticated-orcid":false,"given":"Noel F. C. C.","family":"de Miranda","sequence":"additional","affiliation":[]},{"given":"Sofia","family":"Mensurado","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4141-9302","authenticated-orcid":false,"given":"Bruno","family":"Silva-Santos","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2025,4,16]]},"reference":[{"key":"948_CR1","doi-asserted-by":"publisher","first-page":"3875","DOI":"10.1007\/s00262-023-03520-5","volume":"72","author":"KX Lin","year":"2023","unstructured":"Lin, K. X. et al. PD-1 and PD-L1 inhibitors in cold colorectal cancer: challenges and strategies. Cancer Immunol. Immunother. 72, 3875\u20133893 (2023).","journal-title":"Cancer Immunol. Immunother."},{"key":"948_CR2","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1038\/nrclinonc.2017.88","volume":"14","author":"M Nishino","year":"2017","unstructured":"Nishino, M., Ramaiya, N. H., Hatabu, H. & Hodi, F. S. Monitoring immune-checkpoint blockade: response evaluation and biomarker development. Nat. Rev. Clin. Oncol. 14, 655\u2013668 (2017).","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"948_CR3","doi-asserted-by":"publisher","first-page":"815","DOI":"10.1038\/s41416-019-0421-x","volume":"120","author":"ME Ijsselsteijn","year":"2019","unstructured":"Ijsselsteijn, M. E. et al. Revisiting immune escape in colorectal cancer in the era of immunotherapy. Br. J. Cancer 120, 815\u2013818 (2019).","journal-title":"Br. J. Cancer"},{"key":"948_CR4","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1038\/s41586-022-05593-1","volume":"613","author":"NL de Vries","year":"2023","unstructured":"de Vries, N. L. et al. \u03b3\u03b4 T cells are effectors of immunotherapy in cancers with HLA class I defects. Nature 613, 743\u2013750 (2023).","journal-title":"Nature"},{"key":"948_CR5","doi-asserted-by":"publisher","first-page":"e125884","DOI":"10.1172\/jci.insight.125884","volume":"4","author":"J Mikulak","year":"2019","unstructured":"Mikulak, J. et al. NKp46-expressing human gut-resident intraepithelial V\u03b41 T cell subpopulation exhibits high antitumor activity against colorectal cancer. JCI Insight 4, e125884 (2019).","journal-title":"JCI Insight"},{"key":"948_CR6","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1038\/s43018-022-00376-z","volume":"3","author":"Y Wu","year":"2022","unstructured":"Wu, Y. et al. A local human V\u03b41 T cell population is associated with survival in nonsmall-cell lung cancer. Nat. Cancer 3, 696\u2013709 (2022).","journal-title":"Nat. Cancer"},{"key":"948_CR7","doi-asserted-by":"publisher","first-page":"eaax9364","DOI":"10.1126\/scitranslmed.aax9364","volume":"11","author":"Y Wu","year":"2019","unstructured":"Wu, Y. et al. An innate-like V\u03b41+ \u03b3\u03b4 T cell compartment in the human breast is associated with remission in triple-negative breast cancer. Sci. Transl. Med. 11, eaax9364 (2019).","journal-title":"Sci. Transl. Med."},{"key":"948_CR8","doi-asserted-by":"publisher","first-page":"420","DOI":"10.1038\/s43018-023-00690-0","volume":"5","author":"D Davies","year":"2024","unstructured":"Davies, D. et al. PD-1 defines a distinct, functional, tissue-adapted state in V\u03b41+ T cells with implications for cancer immunotherapy. Nat. Cancer 5, 420\u2013432 (2024).","journal-title":"Nat. Cancer"},{"key":"948_CR9","doi-asserted-by":"publisher","first-page":"e1347742","DOI":"10.1080\/2162402X.2017.1347742","volume":"6","author":"S Meraviglia","year":"2017","unstructured":"Meraviglia, S. et al. Distinctive features of tumor-infiltrating \u03b3\u03b4 T lymphocytes in human colorectal cancer. Oncoimmunology 6, e1347742 (2017).","journal-title":"Oncoimmunology"},{"key":"948_CR10","doi-asserted-by":"publisher","first-page":"1684","DOI":"10.1002\/ijc.34669","volume":"153","author":"L Yu","year":"2023","unstructured":"Yu, L. et al. Tumor\u2010infiltrating \u03b3\u03b4 T\u2010cells reveal exhausted subsets with remarkable heterogeneity in colorectal cancer. Int. J. Cancer 153, 1684\u20131697 (2023).","journal-title":"Int. J. Cancer"},{"key":"948_CR11","doi-asserted-by":"publisher","first-page":"1122","DOI":"10.1038\/s43018-023-00589-w","volume":"4","author":"C Harmon","year":"2023","unstructured":"Harmon, C. et al. \u03b3\u03b4 T cell dichotomy with opposing cytotoxic and wound healing functions in human solid tumors. Nat. Cancer 4, 1122\u20131137 (2023).","journal-title":"Nat. Cancer"},{"key":"948_CR12","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1038\/s41571-022-00722-1","volume":"20","author":"S Mensurado","year":"2023","unstructured":"Mensurado, S., Blanco-Dom\u00ednguez, R. & Silva-Santos, B. The emerging roles of \u03b3\u03b4 T cells in cancer immunotherapy. Nat. Rev. Clin. Oncol. 20, 178\u2013191 (2023).","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"948_CR13","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1038\/s41590-023-01429-w","volume":"24","author":"B Silva-Santos","year":"2023","unstructured":"Silva-Santos, B. & Mensurado, S. \u03b3\u03b4 T cells maintain sensitivity to immunotherapy in MHC-I-deficient tumors. Nat. Immunol. 24, 387\u2013388 (2023).","journal-title":"Nat. Immunol."},{"key":"948_CR14","doi-asserted-by":"publisher","first-page":"5795","DOI":"10.1158\/1078-0432.CCR-16-0597","volume":"22","author":"AR Almeida","year":"2016","unstructured":"Almeida, A. R. et al. Delta One T cells for immunotherapy of chronic lymphocytic leukemia: clinical-grade expansion\/differentiation and preclinical proof of concept. Clin. Cancer Res. 22, 5795\u20135804 (2016).","journal-title":"Clin. Cancer Res."},{"key":"948_CR15","doi-asserted-by":"publisher","first-page":"992","DOI":"10.1182\/blood-2011-02-339135","volume":"118","author":"DV Correia","year":"2011","unstructured":"Correia, D. V. et al. Differentiation of human peripheral blood V\u03b41+ T cells expressing the natural cytotoxicity receptor NKp30 for recognition of lymphoid leukemia cells. Blood 118, 992\u20131001 (2011).","journal-title":"Blood"},{"key":"948_CR16","doi-asserted-by":"publisher","first-page":"552","DOI":"10.1158\/2326-6066.CIR-18-0647","volume":"7","author":"B Di Lorenzo","year":"2019","unstructured":"Di Lorenzo, B. et al. Broad cytotoxic targeting of acute myeloid leukemia by polyclonal Delta One T cells. Cancer Immunol. Res. 7, 552\u2013558 (2019).","journal-title":"Cancer Immunol. Res."},{"key":"948_CR17","doi-asserted-by":"publisher","first-page":"1488","DOI":"10.1182\/blood.2023022992","volume":"143","author":"S Mensurado","year":"2024","unstructured":"Mensurado, S. et al. CD155\/PVR determines acute myeloid leukemia targeting by Delta One T cells. Blood 143, 1488\u20131495 (2024).","journal-title":"Blood"},{"key":"948_CR18","doi-asserted-by":"publisher","first-page":"e005400","DOI":"10.1136\/jitc-2022-005400","volume":"10","author":"D S\u00e1nchez Mart\u00ednez","year":"2022","unstructured":"S\u00e1nchez Mart\u00ednez, D. et al. Generation and proof-of-concept for allogeneic CD123 CAR-Delta One T (DOT) cells in acute myeloid leukemia. J. Immunother. Cancer 10, e005400 (2022).","journal-title":"J. Immunother. Cancer"},{"key":"948_CR19","doi-asserted-by":"publisher","first-page":"2671","DOI":"10.3390\/cancers16152671","volume":"16","author":"D van der Graaff","year":"2024","unstructured":"van der Graaff, D. et al. Advancements in research and treatment applications of patient-derived tumor organoids in colorectal cancer. Cancers (Basel) 16, 2671 (2024).","journal-title":"Cancers (Basel)"},{"key":"948_CR20","doi-asserted-by":"publisher","first-page":"1045024","DOI":"10.3389\/fimmu.2023.1045024","volume":"14","author":"K Zhang","year":"2023","unstructured":"Zhang, K. et al. Bright future or blind alley? CAR-T cell therapy for solid tumors. Front. Immunol. 14, 1045024 (2023).","journal-title":"Front. Immunol."},{"key":"948_CR21","doi-asserted-by":"publisher","first-page":"1352805","DOI":"10.3389\/fimmu.2024.1352805","volume":"15","author":"V Albarr\u00e1n","year":"2024","unstructured":"Albarr\u00e1n, V. et al. Adoptive T cell therapy for solid tumors: current landscape and future challenges. Front. Immunol. 15, 1352805 (2024).","journal-title":"Front. Immunol."},{"key":"948_CR22","doi-asserted-by":"publisher","first-page":"713158","DOI":"10.3389\/fimmu.2021.713158","volume":"12","author":"MB Fuertes","year":"2021","unstructured":"Fuertes, M. B., Domaica, C. I. & Zwirner, N. W. Leveraging NKG2D ligands in immuno-oncology. Front. Immunol. 12, 713158 (2021).","journal-title":"Front. Immunol."},{"key":"948_CR23","doi-asserted-by":"publisher","first-page":"5069","DOI":"10.3390\/ijms24065069","volume":"24","author":"S Gomes","year":"2023","unstructured":"Gomes, S., Rodrigues, A. C., Pazienza, V. & Preto, A. Modulation of the tumor microenvironment by microbiota-derived short-chain fatty acids: impact in colorectal cancer therapy. Int. J. Mol. Sci. 24, 5069 (2023).","journal-title":"Int. J. Mol. Sci."},{"key":"948_CR24","doi-asserted-by":"publisher","first-page":"988","DOI":"10.1016\/j.cmet.2021.03.002","volume":"33","author":"Y He","year":"2021","unstructured":"He, Y. et al. Gut microbial metabolites facilitate anticancer therapy efficacy by modulating cytotoxic CD8+ T cell immunity. Cell Metab. 33, 988\u20131000 (2021).","journal-title":"Cell Metab."},{"key":"948_CR25","doi-asserted-by":"publisher","first-page":"612","DOI":"10.1038\/s41590-023-01448-7","volume":"24","author":"C Rancan","year":"2023","unstructured":"Rancan, C. et al. Exhausted intratumoral V\u03b42\u2212 \u03b3\u03b4 T cells in human kidney cancer retain effector function. Nat. Immunol. 24, 612\u2013624 (2023).","journal-title":"Nat. Immunol."},{"key":"948_CR26","doi-asserted-by":"publisher","DOI":"10.1186\/s40364-020-00228-x","volume":"8","author":"D Jorgovanovic","year":"2020","unstructured":"Jorgovanovic, D., Song, M., Wang, L. & Zhang, Y. Roles of IFN-\u03b3 in tumor progression and regression: a review. Biomark. Res. 8, 49 (2020).","journal-title":"Biomark. Res."},{"key":"948_CR27","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1016\/j.immuni.2022.02.005","volume":"55","author":"KL Banta","year":"2022","unstructured":"Banta, K. L. et al. Mechanistic convergence of the TIGIT and PD-1 inhibitory pathways necessitates co-blockade to optimize anti-tumor CD8+ T cell responses. Immunity 55, 512\u2013526 (2022).","journal-title":"Immunity"},{"key":"948_CR28","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1111\/j.1365-2249.1995.tb06651.x","volume":"102","author":"N Watanabe","year":"1995","unstructured":"Watanabe, N., Hizuta, A., Tanaka, N. & Orita, K. Localization of T cell receptor (TCR)-\u03b3\u03b4+ T cells into human colorectal cancer: flow cytometric analysis of TCR-\u03b3\u03b4 expression in tumour-infiltrating lymphocytes. Clin. Exp. Immunol. 102, 167\u2013173 (1995).","journal-title":"Clin. Exp. Immunol."},{"key":"948_CR29","doi-asserted-by":"publisher","first-page":"1681","DOI":"10.1084\/jem.183.4.1681","volume":"183","author":"MJ Maeurer","year":"1996","unstructured":"Maeurer, M. J. et al. Human intestinal V\u03b41+ lymphocytes recognize tumor cells of epithelial origin. J. Exp. Med. 183, 1681\u20131696 (1996).","journal-title":"J. Exp. Med."},{"key":"948_CR30","doi-asserted-by":"publisher","first-page":"1949","DOI":"10.1056\/NEJMoa2400634","volume":"390","author":"M Chalabi","year":"2024","unstructured":"Chalabi, M. et al. Neoadjuvant immunotherapy in locally advanced mismatch repair-deficient colon cancer. N. Engl. J. Med. 390, 1949\u20131958 (2024).","journal-title":"N. Engl. J. Med."},{"key":"948_CR31","doi-asserted-by":"publisher","first-page":"3511","DOI":"10.1200\/JCO.2022.40.16_suppl.3511","volume":"40","author":"YL Verschoor","year":"2022","unstructured":"Verschoor, Y. L. et al. Neoadjuvant nivolumab, ipilimumab, and celecoxib in MMR-proficient and MMR-deficient colon cancers: final clinical analysis of the NICHE study. J. Clin. Oncol. 40, 3511\u20133511 (2022).","journal-title":"J. Clin. Oncol."},{"key":"948_CR32","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/19490976.2021.1907272","volume":"13","author":"MK Stoeva","year":"2021","unstructured":"Stoeva, M. K. et al. Butyrate-producing human gut symbiont, Clostridium butyricum, and its role in health and disease. Gut Microbes 13, 1\u201328 (2021).","journal-title":"Gut Microbes"},{"key":"948_CR33","doi-asserted-by":"publisher","first-page":"1103836","DOI":"10.3389\/fmicb.2022.1103836","volume":"13","author":"V Singh","year":"2022","unstructured":"Singh, V. et al. Butyrate producers, \u2018the sentinel of gut\u2019: their intestinal significance with and beyond butyrate, and prospective use as microbial therapeutics. Front. Microbiol. 13, 1103836 (2022).","journal-title":"Front. Microbiol."},{"key":"948_CR34","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1136\/gutjnl-2019-318672","volume":"69","author":"NL de Vries","year":"2020","unstructured":"de Vries, N. L. et al. High-dimensional cytometric analysis of colorectal cancer reveals novel mediators of antitumour immunity. Gut 69, 691\u2013703 (2020).","journal-title":"Gut"},{"key":"948_CR35","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-45449-y","volume":"15","author":"SC Lien","year":"2024","unstructured":"Lien, S. C. et al. Tumor reactive \u03b3\u03b4 T cells contribute to a complete response to PD-1 blockade in a Merkel cell carcinoma patient. Nat. Commun. 15, 1094 (2024).","journal-title":"Nat. Commun."},{"key":"948_CR36","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-51025-1","volume":"15","author":"V Stary","year":"2024","unstructured":"Stary, V. et al. Dysfunctional tumor-infiltrating V\u03b41+ T lymphocytes in microsatellite-stable colorectal cancer. Nat. Commun. 15, 6949 (2024).","journal-title":"Nat. Commun."},{"key":"948_CR37","doi-asserted-by":"publisher","first-page":"1552","DOI":"10.1038\/s41590-020-0791-5","volume":"21","author":"G Galletti","year":"2020","unstructured":"Galletti, G. et al. Two subsets of stem-like CD8+ memory T cell progenitors with distinct fate commitments in humans. Nat. Immunol. 21, 1552\u20131562 (2020).","journal-title":"Nat. Immunol."},{"key":"948_CR38","doi-asserted-by":"publisher","first-page":"9503","DOI":"10.1200\/JCO.2020.38.15_suppl.9503","volume":"38","author":"D Rodriguez-Abreu","year":"2020","unstructured":"Rodriguez-Abreu, D. et al. Primary analysis of a randomized, double-blind, phase II study of the anti-TIGIT antibody tiragolumab (tira) plus atezolizumab (atezo) versus placebo plus atezo as first-line (1L) treatment in patients with PD-L1-selected NSCLC (CITYSCAPE). J. Clin. Oncol. 38, 9503\u20139503 (2020).","journal-title":"J. Clin. Oncol."},{"key":"948_CR39","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/bs.mcb.2024.08.008","volume":"190","author":"S Mensurado","year":"2024","unstructured":"Mensurado, S., Blanco-Dom\u00ednguez, R., Carreira, M., Barros, L. & Silva-Santos, B.Processing human colon cancer specimens for in vitro cytotoxicity assays. Methods Cell Biol. 190, 105\u2013117 (2024).","journal-title":"Methods Cell Biol."},{"key":"948_CR40","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/bs.mcb.2024.08.009","volume":"190","author":"R Blanco-Dom\u00ednguez","year":"2024","unstructured":"Blanco-Dom\u00ednguez, R., Mensurado, S., Barros, L., Carreira, M. & Silva-Santos, B.An orthotopic metastatic xenograft model of colorectal cancer. Methods Cell Biol. 190, 119\u2013132 (2024).","journal-title":"Methods Cell Biol."},{"key":"948_CR41","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-016-1012-2","volume":"17","author":"M Haeussler","year":"2016","unstructured":"Haeussler, M. et al. Evaluation of off-target and on-target scoring algorithms and integration into the guide RNA selection tool CRISPOR. Genome Biol. 17, 148 (2016).","journal-title":"Genome Biol."},{"key":"948_CR42","doi-asserted-by":"publisher","first-page":"e69","DOI":"10.1002\/cpim.69","volume":"124","author":"SA Oh","year":"2019","unstructured":"Oh, S. A., Seki, A. & Rutz, S. Ribonucleoprotein transfection for CRISPR\/Cas9\u2010mediated gene knockout in primary T cells. Curr. Protoc. Immunol. 124, e69 (2019).","journal-title":"Curr. Protoc. Immunol."},{"key":"948_CR43","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.chroma.2017.04.052","volume":"1503","author":"LG Johnsen","year":"2017","unstructured":"Johnsen, L. G., Skou, P. B., Khakimov, B. & Bro, R. Gas chromatography\u2013mass spectrometry data processing made easy. J. Chromatogr. A 1503, 57\u201364 (2017).","journal-title":"J. Chromatogr. A"}],"container-title":["Nature Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s43018-025-00948-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s43018-025-00948-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s43018-025-00948-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T10:02:31Z","timestamp":1750932151000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s43018-025-00948-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,16]]},"references-count":43,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["948"],"URL":"https:\/\/doi.org\/10.1038\/s43018-025-00948-9","relation":{},"ISSN":["2662-1347"],"issn-type":[{"value":"2662-1347","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,16]]},"assertion":[{"value":"16 May 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 March 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 April 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"B.S.-S., R.B.-D., L.B., M.C., S.M., and C.C. received funding from a sponsored research agreement with Takeda Development Center Americas. The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}