{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T07:11:55Z","timestamp":1792566715510,"version":"4.5.0"},"reference-count":57,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"18","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2025,5,2]]},"abstract":"<jats:p>\n                    Human induced pluripotent stem cells (iPSCs) offer a promising source for chimeric antigen receptor (CAR)\u2013engineered natural killer (NK) products. However, complex iPSC-NK (iNK) manufacturing challenges clinical use. Here, we identified LiPSC-GR1.1 as a superior iPSC line for iNK production. By engineering LiPSC-GR1.1 with a mesothelin (MSLN)\u2013targeting CAR and interleukin-15 (IL-15), we achieved robust differentiation of iPSCs into mature activated iNK cells with enhanced tumor killing efficacy, superior tumor homing, and vigorous proliferation. Single-cell transcriptomic analysis revealed that transforming growth factor\u2013\u03b2 (TGF-\u03b2)\u2013producing tumor cells up-regulated major histocompatibility complex molecules and down-regulated MSLN post\u2013CAR-IL-15 iNK treatment. Tumor-infiltrating CAR-IL-15 iNK cells exhibited high levels of CAR, IL-15, and NK-activating receptors, negligible checkpoint exhaustion markers, and extremely low levels of NK suppressive factors\n                    <jats:italic toggle=\"yes\">CISH<\/jats:italic>\n                    ,\n                    <jats:italic toggle=\"yes\">TGFBR2<\/jats:italic>\n                    , and\n                    <jats:italic toggle=\"yes\">BATF<\/jats:italic>\n                    , enabling them to sustain activation, metabolic fitness, and effective tumor killing within TGF-\u03b2\u2013rich hypoxic tumor microenvironment. Overall, we developed MSLN.CAR-IL-15\u2013engineered GR1.1-iNK therapy with enhanced antitumor efficacy for solid tumor treatment.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.adt9932","type":"journal-article","created":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T13:58:36Z","timestamp":1746194316000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":15,"title":["Robust differentiation of NK cells from MSLN.CAR-IL-15\u2013engineered human iPSCs with enhanced antitumor efficacy against solid tumors"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1611-2595","authenticated-orcid":true,"given":"Qun","family":"Jiang","sequence":"first","affiliation":[{"name":"Thoracic and GI Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiming","family":"Yu","sequence":"additional","affiliation":[{"name":"Lymphocyte Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD, USA."},{"name":"Center for Advanced Tissue Imaging, NIAID and NCI, NIH, Bethesda, MD, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-2339-3785","authenticated-orcid":true,"given":"James","family":"Ma","sequence":"additional","affiliation":[{"name":"University of Pittsburgh School of Medicine, Pittsburgh, PA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingming","family":"Zhao","sequence":"additional","affiliation":[{"name":"Thoracic and GI Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1021-0549","authenticated-orcid":true,"given":"Jizhong","family":"Zou","sequence":"additional","affiliation":[{"name":"iPSC Core, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sameer","family":"Mir","sequence":"additional","affiliation":[{"name":"Thoracic and GI Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8590-5233","authenticated-orcid":true,"given":"Jingli","family":"Zhang","sequence":"additional","affiliation":[{"name":"Thoracic and GI Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, 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