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Although \u03b3\u03b4 T cells are abundant in the skin, their therapeutic value in skin cancer has remained largely unexplored due to challenges in isolating sufficient numbers of \u03b3\u03b4 T cells from human tissues and a lack of suitable preclinical models for skin cancer. Here, we are using innovative methods to expand human cutaneous \u03b3\u03b4 T cells ex vivo, enabling us to investigate their therapeutic potential in a human cutaneous squamous cell carcinoma (cSCC) mouse model. In this model, \u03b3\u03b4 T cells were specifically recruited to and maintained in the cSCC xenograft. These tumor-infiltrating cells exhibited an activated, cytotoxic phenotype and demonstrated effective antitumor activity in vivo. Collectively, our findings provide preclinical evidence supporting human skin\u2013resident \u03b3\u03b4 T cells as a promising immunotherapeutic approach for treating skin cancers such as cSCC.<\/jats:p>","DOI":"10.1126\/sciadv.aec7215","type":"journal-article","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T18:00:04Z","timestamp":1782324004000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Harnessing skin-resident \u03b3\u03b4 T cells for immunotherapy in cutaneous squamous cell carcinoma"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2575-8075","authenticated-orcid":true,"given":"Giorgia","family":"Nasi","sequence":"first","affiliation":[{"name":"Department of Biosciences and Medical Biology, University of Salzburg, Salzburg, 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