{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T01:09:53Z","timestamp":1791421793781,"version":"4.3.3"},"reference-count":137,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,3,21]],"date-time":"2025-03-21T00:00:00Z","timestamp":1742515200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Gamma delta (\u03b3\u03b4) T cells are a unique subset of T lymphocytes with distinctive features that make them highly promising candidates for cancer therapy. Their MHC-independent recognition of tumor antigens, ability to mediate direct cytotoxicity, and role in modulating the tumor microenvironment position them as versatile agents in cancer immunotherapy. This review integrates and synthesizes the existing data on \u03b3\u03b4 T cells, with an emphasis on the development and optimization of in vitro expansion protocols. Critical aspects are detailed such as activation strategies, co-culture systems, cytokine use, and other parameters to ensure robust cell proliferation and functionality, which may be valuable for those developing or optimizing clinical practices. Finally, we discuss current advancements in \u03b3\u03b4 T cell research, clinical experience, and highlight areas needing further exploration. Considering these data, we hypothesize and propose potential new applications such as engineering \u03b3\u03b4 T cells for enhanced resistance to immune checkpoint pathways or for localized cytokine delivery within the tumor microenvironment, which could broaden their therapeutic impact in the treatment of cancer and beyond.<\/jats:p>","DOI":"10.3390\/cancers17071063","type":"journal-article","created":{"date-parts":[[2025,3,24]],"date-time":"2025-03-24T04:48:18Z","timestamp":1742791698000},"page":"1063","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["\u03b3\u03b4 T Cells: Game Changers in Immune Cell Therapy for Cancer"],"prefix":"10.3390","volume":"17","author":[{"given":"Nabil","family":"Subhi-Issa","sequence":"first","affiliation":[{"name":"Department of Immunology, Hospital Cl\u00ednico San Carlos, IdISSC, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1797-5321","authenticated-orcid":false,"given":"Daniel","family":"Tovar Manzano","sequence":"additional","affiliation":[{"name":"Department of Immunology, Hospital Cl\u00ednico San Carlos, IdISSC, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandro","family":"Pereiro Rodriguez","sequence":"additional","affiliation":[{"name":"Department of Immunology, Hospital Cl\u00ednico San Carlos, IdISSC, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9585-6167","authenticated-orcid":false,"given":"Silvia","family":"Sanchez Ramon","sequence":"additional","affiliation":[{"name":"Department of Immunology, Hospital Cl\u00ednico San Carlos, IdISSC, 28040 Madrid, Spain"},{"name":"Department of Immunology, Ophthalmology, and ORL, School of Medicine, Complutense University, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro","family":"Perez Segura","sequence":"additional","affiliation":[{"name":"Department of Oncology, Hospital Cl\u00ednico San Carlos, IdISSC, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1067-9630","authenticated-orcid":false,"given":"Alberto","family":"Oca\u00f1a","sequence":"additional","affiliation":[{"name":"Department of Oncology, Hospital Cl\u00ednico San Carlos, IdISSC, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1016\/0008-8749(90)90053-T","article-title":"\u0393\u03b4 T Cells in the Human Intestine Express Surface Markers of Activation and Are Preferentially Located in the Epithelium","volume":"128","author":"Ullrich","year":"1990","journal-title":"Cell. 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