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This phase 1b\/2 trial evaluated the safety and efficacy of allogeneic NK cell therapy combined with gemcitabine and S-1 as a first-line treatment for advanced pancreatic cancer (APC) and explored the dynamic responsive immune landscape (ChiCTR1900021764). The administration of 1 \u00d7 10\n                    <jats:sup>9<\/jats:sup>\n                    to 8 \u00d7 10\n                    <jats:sup>9<\/jats:sup>\n                    NK cells to 24 patients was well tolerated, with no graft-versus-host disease or dose-limiting toxicity. Among the 19 evaluable patients, the objective response rate was 31.6%, and the disease control rate was 73.7%. The median progression-free survival was 6.6 months, and the overall survival was 10.8 months. Further longitudinal single-cell RNA sequencing (scRNA-seq) of 19 paired-blood samples revealed an increased proportion of certain NK cell subsets (c4-ZEB2, c5-IL7, c6-IL15, c10-NCR3, and c11-TNFSF8) and T-cell subsets (CD8\n                    <jats:sup>+<\/jats:sup>\n                    Teff and CD4\n                    <jats:sup>+<\/jats:sup>\n                    Tem) in responders, characterized by increased expression of proinflammatory and effector molecules. Bulk T-cell receptor (TCR) V\u03b2 repertoire sequencing of responders indicated potential T-cell clonal expansion, manifested as a greater abundance of large and hyperexpanded clonotypes. Our first-in-human trial demonstrated its safety and potentially preliminary efficacy, warranting further clinical evaluation. Multiomic profiling identified specific circulating NK and T-cell subsets potentially associated with clinical outcomes, providing novel insights into the dynamic transcriptional underpinnings of the immune landscape in response to NK cell-based therapy.\n                  <\/jats:p>","DOI":"10.1038\/s41392-025-02488-1","type":"journal-article","created":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T23:02:37Z","timestamp":1763679757000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Dynamic transcriptional immune landscape in response to NK-cell therapy combined with gemcitabine plus S-1 in advanced pancreatic cancer: a phase 1b\/2 trial"],"prefix":"10.1038","volume":"10","author":[{"given":"Qin","family":"Tan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifei","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caixia","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinlian","family":"Tong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiangyong","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingying","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueqing","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sen","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2054-901X","authenticated-orcid":false,"given":"Fei","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunbo","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,21]]},"reference":[{"key":"2488_CR1","first-page":"12","volume":"74","author":"RL Siegel","year":"2024","unstructured":"Siegel, R. 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