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The TGF-βR1 inhibitor galunisertib re-shapes the PDAC-TME by limiting decidual-like natural killer cells polarization
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  • Published: 31 March 2026

The TGF-βR1 inhibitor galunisertib re-shapes the PDAC-TME by limiting decidual-like natural killer cells polarization

  • Martina Cucchiara1,2 na1,
  • Maria Teresa Palano  ORCID: orcid.org/0000-0002-0867-95271 na1,
  • Cristian Rubuano1 na1,
  • Gianluca De Antoni1,2,
  • Matteo Gallazzi1,
  • Daniele Mercatelli  ORCID: orcid.org/0000-0003-3228-05803,
  • Marta Tagliabue4,
  • Adelaide Pessi4,
  • Gianpiero Catalano  ORCID: orcid.org/0000-0002-1550-26825,
  • Maria Gemelli4,
  • Riccardo Ricotta4,
  • Pier Francesco Ferrucci4,
  • Gennaro Nappo6,7,
  • Silvia Uccella7,8,
  • Alessandro Zerbi6,7,
  • Patrizia Borsotti9,
  • Giulia Garattini9,
  • Federica Di Leva9,
  • Nicolò Baranzini10,
  • Annalisa Grimaldi10,
  • Lorenzo Mortara1,2,
  • Francesco Acquati11,
  • Paola Cornelia Muti12,13,
  • Dorina Belotti  ORCID: orcid.org/0000-0002-3868-91449,
  • Andrea Resovi9 na2,
  • Barbara Bassani1 na2 &
  • …
  • Antonino Bruno  ORCID: orcid.org/0000-0002-4790-08611,2 na2 

Cell Death & Disease , Article number:  (2026) Cite this article

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We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • Oncogenesis
  • Pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related mortality worldwide. Natural Killer (NKs) cells are pivotal for tumor surveillance but are dysfunctional in PDAC. We evaluated whether pharmacological blockade of TGF-β1/TGF-βR1 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-β1/ TGF-βR1 levels than HC, with worse outcomes in TGF-β1high/TGF-βR1high patients. Circulating CD9+ 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 Hirudo verbana), compared to the CD9- NK cells. PDAC cells and CAF induced a CD9+-decidual-like phenotype, also impairing NK degranulation. GAL treatment restrains PDAC cell/CAF-induced NK anergy, restoring their cytotoxicity. Also, TGFβ-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 FGF2, HGF, IL11, PLGF, EGFR, and VEGF. In vivo in orthotopic tumors formed by FC1199 cells GAL decreased CD9+-NK frequency, promoted M1-macrophage polarization, and activated NK and CD8+T-cells, together with a significant reduction of tumor weight, fibrosis and inhibition of angiogenesis. Our study identifies CD9+NKs as a novel cell subset expanded in PDAC and underscores the role of TGF-β1/TGF-βR1 signalling in promoting a pro-tumoral NKs GAL-treatment emerges as immunomodulator able in re-educating pro-tumor NKs cells in PDAC.

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Data availability

The data supporting the findings of the study are available, by the corresponding authors, upon reasonable requests. In-silico analyses were performed using publicly available datasets. All datasets interrogated are reported in the “Dataset interrogation” paragraph of Material and Methods section.

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Acknowledgements

We thank David Tuveson for kindly providing the FC1199 cell line. We thank the Flow Cytometry Facility F.L.O.R.A.L., at IRCCS MultiMedica, Milan, Italy, and its facility manager, Ivan Muradore, for cell-sorting assistance.

Funding

The study has been funded by Fondazione Cariplo to AR and AB (ID: 2019-1609); a grant funded by the Italian Ministry of University and Research PRIN 2022 (ID: 2022RK9X2K), to AB, by the Associazione Italiana per la Ricerca sul Cancro (AIRC) IG 2019 (ID 23443) to DB, by the Guido Berlucchi Foundation Mini-Grant CUP number “F43C24000460007”, to BB, and by the Fondo di Ateneo per la Ricerca (FAR)-University of Insubria, Varese, Italy, FAR 2022 to AB and by FAR 2023 to LM. MC, MTP, CR, MGa, BB, and AB are funded by the Ricerca Corrente, IRCCS MultiMedica. MC was a participant in the PhD Program in Experimental and Translational Medicine, at the University of Insubria, Varese, Italy. GdA is a participant in the PhD Progam in Life Science and Biotecnology CR was funded by an Assegno di Ricerca on a grant funded by the Italian Ministry of University and Research PRIN 2022 (ID: 2022RK9X2K), to AB. FDiL is funded by an Assegno di Ricerca on a grant funded by the Italian Ministry of University and Research PRIN 2022 (ID: 2022RK9X2K), to AB.

Author information

Author notes

  1. These authors contributed equally: Martina Cucchiara, Maria Teresa Palano, Cristian Rubuano.

  2. These authors jointly supervised this work: Andrea Resovi, Barbara Bassani, Antonino Bruno.

Authors and Affiliations

  1. Laboratory of Innate Immunity, IRCCS MultiMedica, Milan, Italy

    Martina Cucchiara, Maria Teresa Palano, Cristian Rubuano, Gianluca De Antoni, Matteo Gallazzi, Lorenzo Mortara, Barbara Bassani & Antonino Bruno

  2. Laboratory of Immunology and General Pathology, Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy

    Martina Cucchiara, Gianluca De Antoni, Lorenzo Mortara & Antonino Bruno

  3. Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy

    Daniele Mercatelli

  4. Medical Oncology Department, IRCCS MultiMedica, Milan, Italy

    Marta Tagliabue, Adelaide Pessi, Maria Gemelli, Riccardo Ricotta & Pier Francesco Ferrucci

  5. Radiation Oncology Center, IRCCS MultiMedica, Milan, Italy

    Gianpiero Catalano

  6. Pancreatic Surgery Unit, Humanitas Clinical and Research Center-IRCCS, Rozzano, Milan, Italy

    Gennaro Nappo & Alessandro Zerbi

  7. Department of Biomedical Sciences, Humanitas University, Rozzano, Milan, Italy

    Gennaro Nappo, Silvia Uccella & Alessandro Zerbi

  8. Department of Pathology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy

    Silvia Uccella

  9. Laboratory of Tumor Microenvironment, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy

    Patrizia Borsotti, Giulia Garattini, Federica Di Leva, Dorina Belotti & Andrea Resovi

  10. Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy

    Nicolò Baranzini & Annalisa Grimaldi

  11. Human Genetics Laboratory, Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy

    Francesco Acquati

  12. IRCCS MultiMedica, Milan, Italy

    Paola Cornelia Muti

  13. Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy

    Paola Cornelia Muti

Authors
  1. Martina Cucchiara
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  2. Maria Teresa Palano
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DB, AR, BB, AB conceived the study, supervised the work, interpreted data, and drafted the manuscript; MC, MTP, CR, GdA, MGa, DM, PB, GG, FDiL, NB, AG, BB, AR, AB performed the experiments and formal analysis; MT, MAP, MGe, RR, PFF, GN, AZ, SU collected and provided clinical samples.

Corresponding authors

Correspondence to Dorina Belotti, Andrea Resovi or Antonino Bruno.

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Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

This study involves human subjects. 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).

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Cucchiara, M., Palano, M.T., Rubuano, C. et al. The TGF-βR1 inhibitor galunisertib re-shapes the PDAC-TME by limiting decidual-like natural killer cells polarization. Cell Death Dis (2026). https://doi.org/10.1038/s41419-026-08581-9

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  • Received: 30 July 2025

  • Revised: 02 February 2026

  • Accepted: 06 March 2026

  • Published: 31 March 2026

  • DOI: https://doi.org/10.1038/s41419-026-08581-9

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