{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T05:08:48Z","timestamp":1774328928009,"version":"3.50.1"},"reference-count":57,"publisher":"BMJ","issue":"11","license":[{"start":{"date-parts":[[2023,11,24]],"date-time":"2023-11-24T00:00:00Z","timestamp":1700784000000},"content-version":"unspecified","delay-in-days":23,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["2021.01953.CEECIND"],"award-info":[{"award-number":["2021.01953.CEECIND"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["PTDC\/MED-ONC\/6829\/2020"],"award-info":[{"award-number":["PTDC\/MED-ONC\/6829\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2023,10,28]]},"published-print":{"date-parts":[[2023,11]]},"abstract":"<jats:p>\u03b3\u03b4 T cells are regarded as promising effector lymphocytes for next-generation cancer immunotherapies. In spite of being relatively rare in human peripheral blood, \u03b3\u03b4 T cells are more abundant in epithelial tissues where many tumors develop, and have been shown to actively participate in anticancer immunity as cytotoxic cells or as \u201ctype 1\u201d immune orchestrators. A major asset of \u03b3\u03b4 T cells for tackling advanced cancers is their independence from antigen presentation via the major histocompatibility complex, which clearly sets them apart from conventional \u03b1\u03b2 T cells. Here we discuss the main therapeutic strategies based on human \u03b3\u03b4 T cells. These include antibody-based bispecific engagers and adoptive cell therapies, either focused on the V\u03b41<jats:sup>+<\/jats:sup> or V\u03b42<jats:sup>+<\/jats:sup> \u03b3\u03b4 T-cell subsets, which can be expanded selectively and differentiated or engineered to maximize their antitumor functions. We review the preclinical data that supports each of the therapeutic strategies under development; and summarize the clinical trials being pursued towards establishing \u03b3\u03b4 T cell-based treatments for solid and hematological malignancies.<\/jats:p>","DOI":"10.1136\/jitc-2023-007955","type":"journal-article","created":{"date-parts":[[2023,11,25]],"date-time":"2023-11-25T00:55:46Z","timestamp":1700873746000},"page":"e007955","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":23,"title":["Therapeutic avenues for \u03b3\u03b4 T cells in cancer"],"prefix":"10.1136","volume":"11","clinical-trial-number":[{"clinical-trial-number":"nct05886491","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04243499","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct05307874","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04887259","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct05369000","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct03183219","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct05886491","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04165941","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct05664243","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct03533816","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct05015426","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct05358808","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct03790072","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct05302037","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04735471","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04911478","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04688853","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04014894","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04864054","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04502082","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04634357","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct05302037","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04735471","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04911478","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04688853","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04014894","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04502082","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04634357","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Gon\u00e7alo Palr\u00e3o","family":"Costa","sequence":"first","affiliation":[{"name":"Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal"}]},{"given":"Sofia","family":"Mensurado","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Molecular Jo\u00e3o Lobo Antunes, Faculade de Medicina, Universidade de Lisboa, Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4141-9302","authenticated-orcid":false,"given":"Bruno","family":"Silva-Santos","sequence":"additional","affiliation":[{"name":"Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal"},{"name":"Instituto de Medicina Molecular Jo\u00e3o Lobo Antunes, Faculade de Medicina, Universidade de Lisboa, Lisbon, Portugal"}]}],"member":"239","published-online":{"date-parts":[[2023,11,24]]},"reference":[{"key":"2025100314101302000_11.11.e007955.1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-18-0367"},{"key":"2025100314101302000_11.11.e007955.2","doi-asserted-by":"crossref","DOI":"10.1186\/s12967-023-04404-z","article-title":"Harnessing the potential of CAR-T cell therapy: progress, challenges, and future directions in hematological and solid tumor treatments","volume":"21","author":"Dagar","year":"2023","journal-title":"J Transl Med"},{"key":"2025100314101302000_11.11.e007955.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2014.01.004"},{"key":"2025100314101302000_11.11.e007955.4","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-019-0153-5"},{"key":"2025100314101302000_11.11.e007955.5","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2022.915837","article-title":"Gamma delta T-cell based cancer immunotherapy: past-present-future","volume":"13","author":"Saura-Esteller","year":"2022","journal-title":"Front Immunol"},{"key":"2025100314101302000_11.11.e007955.6","article-title":"Molecules and mechanisms implicated in the peculiar antigenic activation process of human V\u03b39V\u03b42 T cells","volume":"5","author":"Harly","year":"2014","journal-title":"Front Immunol"},{"key":"2025100314101302000_11.11.e007955.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.02.013"},{"key":"2025100314101302000_11.11.e007955.8","doi-asserted-by":"publisher","DOI":"10.1126\/science.1063916"},{"key":"2025100314101302000_11.11.e007955.9","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-16-0597"},{"key":"2025100314101302000_11.11.e007955.10","doi-asserted-by":"publisher","DOI":"10.1084\/jem.187.12.2065"},{"key":"2025100314101302000_11.11.e007955.11","doi-asserted-by":"publisher","DOI":"10.1084\/jem.188.5.953"},{"key":"2025100314101302000_11.11.e007955.12","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-09-0327"},{"key":"2025100314101302000_11.11.e007955.13","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-019-0038-z"},{"key":"2025100314101302000_11.11.e007955.14","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.24.021605.090542"},{"key":"2025100314101302000_11.11.e007955.15","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.23.021704.115658"},{"key":"2025100314101302000_11.11.e007955.16","doi-asserted-by":"publisher","DOI":"10.1126\/science.1110267"},{"key":"2025100314101302000_11.11.e007955.17","doi-asserted-by":"publisher","DOI":"10.1038\/35081115"},{"key":"2025100314101302000_11.11.e007955.18","doi-asserted-by":"publisher","DOI":"10.1038\/nri1842"},{"key":"2025100314101302000_11.11.e007955.19","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20031981"},{"key":"2025100314101302000_11.11.e007955.20","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80222-8"},{"key":"2025100314101302000_11.11.e007955.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2004.07.034"},{"key":"2025100314101302000_11.11.e007955.22","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-031210-101324"},{"key":"2025100314101302000_11.11.e007955.23","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-07-234211"},{"key":"2025100314101302000_11.11.e007955.24","doi-asserted-by":"publisher","DOI":"10.1084\/jem.190.10.1505"},{"key":"2025100314101302000_11.11.e007955.25","doi-asserted-by":"publisher","DOI":"10.1084\/jem.189.5.787"},{"key":"2025100314101302000_11.11.e007955.26","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-03-006700"},{"key":"2025100314101302000_11.11.e007955.27","doi-asserted-by":"crossref","DOI":"10.1038\/s41590-019-0358-5","article-title":"Publisher correction: \u03b3\u03b4 TCR ligands: the quest to solve a 500-million-year-old mystery","volume":"20","author":"Willcox","year":"2019","journal-title":"Nat Immunol"},{"key":"2025100314101302000_11.11.e007955.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2017.10.009"},{"key":"2025100314101302000_11.11.e007955.29","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05593-1"},{"key":"2025100314101302000_11.11.e007955.30","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1038\/s41590-023-01429-w","article-title":"\u03b3\u03b4 T cells maintain sensitivity to Immunotherapy in MHC-I-deficient tumors","volume":"24","author":"Silva-Santos","year":"2023","journal-title":"Nat Immunol"},{"key":"2025100314101302000_11.11.e007955.31","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1038\/s41590-023-01448-7","article-title":"Exhausted Intratumoral V\u03b42\u2212 \u03b3\u03b4 T cells in human kidney cancer retain effector function","volume":"24","author":"Rancan","year":"2023","journal-title":"Nat Immunol"},{"key":"2025100314101302000_11.11.e007955.32","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-13-0675"},{"key":"2025100314101302000_11.11.e007955.33","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-20-0138"},{"key":"2025100314101302000_11.11.e007955.34","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-20-4576"},{"key":"2025100314101302000_11.11.e007955.35","doi-asserted-by":"crossref","first-page":"2274","DOI":"10.1038\/s41375-021-01122-7","article-title":"Selective recruitment of \u03b3\u03b4 T cells by a bispecific antibody for the treatment of acute myeloid leukemia","volume":"35","author":"Ganesan","year":"2021","journal-title":"Leukemia"},{"key":"2025100314101302000_11.11.e007955.36","doi-asserted-by":"crossref","DOI":"10.1136\/jitc-2021-003850","article-title":"Gamma Delta TCR anti-CD3 Bispecific molecules (GABs) as novel immunotherapeutic compounds","volume":"9","author":"van Diest","year":"2021","journal-title":"J Immunother Cancer"},{"key":"2025100314101302000_11.11.e007955.37","doi-asserted-by":"crossref","first-page":"83392","DOI":"10.18632\/oncotarget.13110","article-title":"CD19-specific triplebody SPM-1 engages NK and \u03b3\u03b4 T cells for rapid and efficient lysis of malignant B-Lymphoid cells","volume":"7","author":"Schiller","year":"2016","journal-title":"Oncotarget"},{"key":"2025100314101302000_11.11.e007955.38","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2018.00800","article-title":"Improving the efficiency of V\u03b39V\u03b42 T-cell immunotherapy in cancer","volume":"9","author":"Hoeres","year":"2018","journal-title":"Front Immunol"},{"key":"2025100314101302000_11.11.e007955.39","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-020-0515-7"},{"key":"2025100314101302000_11.11.e007955.40","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-18-0647"},{"key":"2025100314101302000_11.11.e007955.41","doi-asserted-by":"crossref","DOI":"10.1136\/jitc-2022-005400","article-title":"Generation and proof-of-concept for allogeneic CD123 CAR-Delta one T (DOT) cells in acute myeloid leukemia","volume":"10","author":"S\u00e1nchez Mart\u00ednez","year":"2022","journal-title":"J Immunother Cancer"},{"key":"2025100314101302000_11.11.e007955.42","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.2004.05077.x"},{"key":"2025100314101302000_11.11.e007955.43","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2012.267"},{"key":"2025100314101302000_11.11.e007955.44","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2017.12.001"},{"key":"2025100314101302000_11.11.e007955.45","first-page":"79","article-title":"MUC1-Tn-targeting Chimeric antigen receptor-modified V\u03b39V\u03b42 T cells with enhanced antigen-specific anti-tumor activity","volume":"11","author":"Zhai","year":"2021","journal-title":"Am J Cancer Res"},{"key":"2025100314101302000_11.11.e007955.46","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1016\/j.omto.2020.04.013","article-title":"Electroporation of NKG2D RNA CAR improves V\u03b39V\u03b42 T cell responses against human solid tumor Xenografts","volume":"17","author":"Ang","year":"2020","journal-title":"Mol Ther Oncolytics"},{"key":"2025100314101302000_11.11.e007955.47","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2022.863155","article-title":"A simple and robust single-step method for CAR-V\u03b41 \u03b3\u03b4T cell expansion and transduction for cancer immunotherapy","volume":"13","author":"Ferry","year":"2022","journal-title":"Front Immunol"},{"key":"2025100314101302000_11.11.e007955.48","doi-asserted-by":"crossref","DOI":"10.1002\/cti2.1373","article-title":"Allogeneic CD20-targeted \u03b3\u03b4 T cells exhibit innate and adaptive antitumor activities in preclinical B-cell lymphoma models","volume":"11","author":"Nishimoto","year":"2022","journal-title":"Clin Transl Immunology"},{"key":"2025100314101302000_11.11.e007955.49","doi-asserted-by":"crossref","DOI":"10.1136\/jitc-2021-003441","article-title":"Off-the-shelf V\u03b41 gamma Delta T cells engineered with Glypican-3 (GPC-3)-specific chimeric antigen receptor (CAR) and soluble IL-15 display robust antitumor efficacy against hepatocellular carcinoma","volume":"9","author":"Makkouk","year":"2021","journal-title":"J Immunother Cancer"},{"key":"2025100314101302000_11.11.e007955.50","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-12-325993"},{"key":"2025100314101302000_11.11.e007955.51","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2018.01062","article-title":"GMP-grade manufacturing of T cells engineered to express a defined \u03b3\u03b4TCR","volume":"9","author":"Straetemans","year":"2018","journal-title":"Front Immunol"},{"key":"2025100314101302000_11.11.e007955.52","doi-asserted-by":"crossref","DOI":"10.1186\/s40425-019-0558-4","article-title":"Evaluating in vivo efficacy - toxicity profile of TEG001 in humanized mice xenografts against primary human AML disease and healthy hematopoietic cells","volume":"7","author":"Johanna","year":"2019","journal-title":"J Immunother Cancer"},{"key":"2025100314101302000_11.11.e007955.53","doi-asserted-by":"crossref","DOI":"10.1038\/s41421-018-0066-6","article-title":"A novel antibody-TCR (AbTCR) platform combines fab-based antigen recognition with gamma\/Delta-TCR signaling to facilitate T-cell cytotoxicity with low cytokine release","volume":"4","author":"Xu","year":"2018","journal-title":"Cell Discov"},{"key":"2025100314101302000_11.11.e007955.54","doi-asserted-by":"crossref","unstructured":"Liu C , Liu H , Dasgupta M , et al . Validation and promise of a TCR mimic antibody for cancer immunotherapy of hepatocellular carcinoma. Sci Rep 2022;12. doi:10.1038\/s41598-022-15946-5","DOI":"10.1038\/s41598-022-15946-5"},{"key":"2025100314101302000_11.11.e007955.55","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.aax9364","article-title":"An innate-like V\u03b41+ \u03b3\u03b4 T cell compartment in the human breast is associated with remission in triple-negative breast cancer","volume":"11","author":"Wu","year":"2019","journal-title":"Sci Transl Med"},{"key":"2025100314101302000_11.11.e007955.56","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1038\/s43018-022-00376-z","article-title":"A local human V\u03b41 T cell population is associated with survival in nonsmall-cell lung cancer","volume":"3","author":"Wu","year":"2022","journal-title":"Nat Cancer"},{"key":"2025100314101302000_11.11.e007955.57","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1038\/s41568-022-00491-0","article-title":"Natural killer cells in antitumour adoptive cell immunotherapy","volume":"22","author":"Laskowski","year":"2022","journal-title":"Nat Rev Cancer"}],"container-title":["Journal for ImmunoTherapy of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jitc-2023-007955","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T21:10:21Z","timestamp":1759525821000},"score":1,"resource":{"primary":{"URL":"https:\/\/jitc.bmj.com\/lookup\/doi\/10.1136\/jitc-2023-007955"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11]]},"references-count":57,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2023,11,24]]},"published-print":{"date-parts":[[2023,11]]}},"alternative-id":["10.1136\/jitc-2023-007955"],"URL":"https:\/\/doi.org\/10.1136\/jitc-2023-007955","relation":{},"ISSN":["2051-1426"],"issn-type":[{"value":"2051-1426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11]]}}}