{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T03:43:52Z","timestamp":1792122232776,"version":"4.4.0"},"reference-count":42,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T00:00:00Z","timestamp":1773878400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100018936","name":"Heidelberg University Hospital","doi-asserted-by":"crossref","award":["SW-P 13749"],"award-info":[{"award-number":["SW-P 13749"]}],"id":[{"id":"10.13039\/501100018936","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable clinical success in B cell malignancies. However, its efficacy in solid tumors remains limited, in part due to suboptimal expansion, persistence, and restrained effector function. Strategies that promote durable CAR-T cell fitness are therefore required to overcome these barriers. In this study, we generated HER2-CAR-T cells targeting human breast cancer cells and evaluated the impact of different cytokine supplementation strategies on CAR-T cell phenotype and function. We analyzed gene expression patterns and performed repetitive tumor killing assays to assess the ability of CAR-T cells expanded with IL-2 + IL-7 + IL-15 compared with IL-2 alone to maintain proliferation and cytotoxic function across multiple rounds of tumor cell exposure. Compared with IL-2 alone, supplementation with IL-7 and IL-15 significantly enhanced CAR-T cell expansion, preserved stem cell-like features prior to antigen encounter, and promoted superior proliferative capacity. Moreover, CAR-T cells cultured with IL-7+15 or IL-2+7+15 maintained sustained cytotoxicity and exhibited increased antitumor cytokine production during repeated tumor challenges. Notably, IL-7 and IL-15 supplementation induced a CD57+ CAR-T cell population that, unlike the immunosenescent CD57+ cells reported previously, retained full proliferative and cytotoxic capacity, with CD57 expression being dynamically downregulated upon antigen stimulation. Collectively, these findings demonstrate that incorporation of IL-7 and IL-15 into CAR-T cell manufacturing protocols substantially improves expansion, persistence, and effector function, supporting their use as a strategy to enhance CAR-T cell performance against solid tumors.<\/jats:p>","DOI":"10.3390\/cells15060547","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T11:50:36Z","timestamp":1773921036000},"page":"547","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Empowerment of CAR-T Cells by IL-7 and IL-15 Boosts Their Efficacy Against HER2-Positive Tumors with Enhanced Expansion and Persistence"],"prefix":"10.3390","volume":"15","author":[{"given":"Zhehong","family":"Cheng","sequence":"first","affiliation":[{"name":"Section of Molecular Immunology, Institute of Immunology, Heidelberg University Hospital, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henning","family":"Kirchgessner","sequence":"additional","affiliation":[{"name":"Section of Molecular Immunology, Institute of Immunology, Heidelberg University Hospital, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beate","family":"Jahraus","sequence":"additional","affiliation":[{"name":"Section of Molecular Immunology, Institute of Immunology, Heidelberg University Hospital, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emre","family":"Balta","sequence":"additional","affiliation":[{"name":"Section of Molecular Immunology, Institute of Immunology, Heidelberg University Hospital, 69120 Heidelberg, Germany"},{"name":"Umbilical Cord Blood, Cell and Tissue Center, STEMBIO, 41400 Kocaeli, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1536-2456","authenticated-orcid":false,"given":"Yvonne","family":"Samstag","sequence":"additional","affiliation":[{"name":"Section of Molecular Immunology, Institute of Immunology, Heidelberg University Hospital, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4099","DOI":"10.1182\/blood-2010-04-281931","article-title":"Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19","volume":"116","author":"Kochenderfer","year":"2010","journal-title":"Blood"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2048","DOI":"10.1158\/1078-0432.CCR-12-2422","article-title":"B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma","volume":"19","author":"Carpenter","year":"2013","journal-title":"Clin. 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