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Natural Killer (NKs) cells are pivotal for tumor surveillance but are dysfunctional in PDAC. We evaluated whether pharmacological blockade of TGF-\u03b21\/TGF-\u03b2R1 axis in PDAC cells and cancer-associated fibroblasts (CAFs) could modulate NK polarization via soluble factors. The phenotype\/functions of NKs from PDAC patients versus healthy controls (HC) were compared, and the polarization state of NKs exposed to the conditioned media of PDAC cells and fibroblasts was evaluated by flow cytometry. The ability of galunisertib (GAL) to reverse NK dysfunction in immunocompetent mice orthotopically implanted with FC1199 PDAC cells was evaluated. PDAC patients showed higher TGF-\u03b21\/ TGF-\u03b2R1 levels than HC, with worse outcomes in TGF-\u03b21\n                    <jats:sup>high<\/jats:sup>\n                    \/TGF-\u03b2R1\n                    <jats:sup>high<\/jats:sup>\n                    patients. Circulating CD9\n                    <jats:sup>+<\/jats:sup>\n                    NKs were expanded in PDAC patients compared with HC and exhibited a pro-angiogenic secretome and higher pro-angiogenic activities in vitro and in vivo (leech Hir\n                    <jats:italic>udo verbana<\/jats:italic>\n                    ), compared to the CD9\n                    <jats:sup>-<\/jats:sup>\n                    NK cells. PDAC cells and CAF induced a CD9\n                    <jats:sup>+<\/jats:sup>\n                    -decidual-like phenotype, also impairing NK degranulation. GAL treatment restrains PDAC cell\/CAF-induced NK anergy, restoring their cytotoxicity. Also, TGF\u03b2-R1 knockdown in PDAC cells exhibited the capability to limit the generation of decidual-like NKs, while restoring their antitumor ability, via soluble factors. Secretome profiling of BxPC3 and MIAPaCA2 PDAC cell lines and CAFs showed that GAL downregulated the release of several growth, angiogenic, and immunoregulatory factors, including\n                    <jats:italic>FGF2, HGF, IL11, PLGF, EGFR<\/jats:italic>\n                    , and\n                    <jats:italic>VEGF<\/jats:italic>\n                    . In vivo in orthotopic tumors formed by FC1199 cells GAL decreased CD9\n                    <jats:sup>+<\/jats:sup>\n                    -NK frequency, promoted M1-macrophage polarization, and activated NK and CD8\n                    <jats:sup>+<\/jats:sup>\n                    T-cells, together with a significant reduction of tumor weight, fibrosis and inhibition of angiogenesis. Our study identifies CD9\n                    <jats:sup>+<\/jats:sup>\n                    NKs as a novel cell subset expanded in PDAC and underscores the role of TGF-\u03b21\/TGF-\u03b2R1 signalling in promoting a pro-tumoral NKs. GAL-treatment emerges as immunomodulator able in re-educating pro-tumor NKs cells in PDAC.\n                  <\/jats:p>","DOI":"10.1038\/s41419-026-08581-9","type":"journal-article","created":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T16:34:53Z","timestamp":1774974893000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The TGF-\u03b2R1 inhibitor galunisertib re-shapes the PDAC-TME by limiting decidual-like natural killer cells polarization"],"prefix":"10.1038","volume":"17","author":[{"given":"Martina","family":"Cucchiara","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0867-9527","authenticated-orcid":false,"given":"Maria Teresa","family":"Palano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristian","family":"Rubuano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianluca","family":"De Antoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Gallazzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3228-0580","authenticated-orcid":false,"given":"Daniele","family":"Mercatelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Tagliabue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adelaide","family":"Pessi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1550-2682","authenticated-orcid":false,"given":"Gianpiero","family":"Catalano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Gemelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riccardo","family":"Ricotta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pier Francesco","family":"Ferrucci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gennaro","family":"Nappo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Uccella","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Zerbi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrizia","family":"Borsotti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Garattini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Di Leva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicol\u00f2","family":"Baranzini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annalisa","family":"Grimaldi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"Mortara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Acquati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola Cornelia","family":"Muti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3868-9144","authenticated-orcid":false,"given":"Dorina","family":"Belotti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Resovi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Bassani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4790-0861","authenticated-orcid":false,"given":"Antonino","family":"Bruno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,31]]},"reference":[{"key":"8581_CR1","doi-asserted-by":"crossref","unstructured":"Advancing on pancreatic cancer. 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The study was approved by the institutional ethics committees of IRCCS MultiMedica (Milan, Italy) protocol number 529\/2022 and by ethics committee IRCCS HUMANITAS (Milan, Italy) protocol number 4128\/2024, according to Helsinki declaration of 1975 and as revised in 2013. All patients signed the informed consent. Procedures involving animals and their care were conducted in conformity with institutional guidelines that comply with national (Lgs 26\/2014) and EU directives laws and policies (EEC Council Directive 2010\/63, in line with guidelines for the welfare and use of animals in cancer research. Animal studies were approved by the Mario Negri Institute Animal Care and Use Committee and by the Italian Ministry of Health (DM 85\/2013-B and Authorization no.125\/2016 PR 519\/2021-PR).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}],"article-number":"577"}}