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High tumor load and substantial residual lesions significantly impair CAR T-cell function and exacerbate cytokine release syndrome (CRS). Here, we report the development of a novel dual cellular immunotherapy in which human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) are co-administered with CD19 CAR T-cells. We demonstrated that this combination therapy enhances the anti-tumor efficacy of CD19 CAR T-cells under high tumor burden condition. In xenograft models of high tumor burden B-cell lymphoma, the dual cellular immunotherapy improved survival, mitigated myelosuppression, and preserved CAR T-cell expansion. Transcriptomic analysis of CAR T-cells revealed enrichment of the Th17 pathway in CAR T-cells, while single-cell RNA sequencing showed enhanced, particularly that of NK-like cytotoxic T lymphocytes characteristics which are associated with Th17 differentiation. Furthermore, in a CRS model, hUC-MSCs attenuate CRS severity by suppressing macrophage activity. Collectively, hUC-MSCs significantly enhance the anti-tumor capability of CD19 CAR T-cells under high tumor burden conditions by inducing CD8\n                    <jats:sup>+<\/jats:sup>\n                    NK-like cytotoxic T lymphocytes through Th17 differentiation, while concurrently mitigating treatment-related side effects. Our study provides a novel therapeutic strategy to improve clinical outcomes in hematological malignancies.\n                  <\/jats:p>","DOI":"10.1038\/s41419-026-08656-7","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T19:03:46Z","timestamp":1774638226000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Th17-driven CD8+ T cells in hUC-MSC and CAR T-cell dual immunotherapy for superior anti-tumor efficacy"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-4721-8682","authenticated-orcid":false,"given":"Caidong","family":"Hu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haixiao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haojie","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jixin","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dabing","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuxian","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuo","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqi","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinhua","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoming","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Chi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhibo","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongchao","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erlie","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guanbin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4438-2544","authenticated-orcid":false,"given":"Jianda","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6604-8937","authenticated-orcid":false,"given":"Ting","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,27]]},"reference":[{"key":"8656_CR1","doi-asserted-by":"publisher","first-page":"S18","DOI":"10.1002\/ajh.25403","volume":"94","author":"A Levin","year":"2019","unstructured":"Levin A, Shah NN. 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Peripheral blood from healthy donors was obtained from the First Affiliated Hospital of Fujian Medical University, with approval from the hospital\u2019s Ethics Committee (approval number: MTCA, ECFAH of FMU [2015] 084-2), and all have obtained informed consent. All animal experiments were performed in accordance with the ethical standards of the Committee on Animal Experimentation and were approved by the Fujian Medical University Animal Care and Use Committee (Approval No: IACUC FJMU 2024-0161).","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"418"}}