Cancer-associated fibroblast subtypes differentially modulate natural killer cells in cancer
8 affiliations
- 1MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK; MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, UK
- 2MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, UK; Helmholtz Institute for Translational Oncology Mainz (HI-TRON Mainz) - a Helmholtz Institute of the DKFZ, Mainz, Germany; German Cancer Research Centre (DKFZ), Division of Dermal Oncoimmunology, Heidelberg, Germany
- 3Helmholtz Institute for Translational Oncology Mainz (HI-TRON Mainz) - a Helmholtz Institute of the DKFZ, Mainz, Germany; German Cancer Research Centre (DKFZ), Division of Dermal Oncoimmunology, Heidelberg, Germany
- 4Institute of Pathology, University Medical Center Mainz, JGU-Mainz 55131 Mainz, Germany; TRON, Translational Oncology at the University Medical Center, JGU-Mainz 55131 Mainz, Germany; Research Center for Immunotherapy, University Medical Center Mainz, JGU-Mainz 55131 Mainz, Germany
- 5Institute of Pathology, University Medical Center Mainz, JGU-Mainz 55131 Mainz, Germany; TRON, Translational Oncology at the University Medical Center, JGU-Mainz 55131 Mainz, Germany
- 6MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK
- 7MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK. Electronic address: [email protected]
- 8MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, UK; Comprehensive Cancer Centre, Kings College London, London, UK; Centre for Cancer Sciences, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, UK. Electronic address: [email protected]
Abstract
Natural killer (NK) cells are cytotoxic innate lymphoid cells which directly kill tumor cells, thus represent an attractive target for immunotherapy. However, NK cells face immunosuppression in the tumor microenvironment (TME), rendering them dysfunctional. While cancer-associated fibroblasts (CAFs) represent an abundant, heterogeneous component of pancreatic ductal adenocarcinoma (PDAC), their interplay with NK cells is largely understudied. Analyzing human samples and employing mouse models of PDAC and functional assays, we observed that intratumoral NK cells are immature, and TGF-β driven myofibroblastic (my)CAFs are strong NK suppressors, in contrast to inflammatory (i)CAF. Furthermore, myCAF-enriched tumor areas excluded NK cells, consistent with their reduced capacity to attract NK cells. Pancreatic CAFs in general reduced NK cell cytotoxicity by direct contact and via soluble factors, including prostaglandin E2 (PGE2). This work reveals distinct and overlapping roles of CAF subpopulations on NK cell functions, suggesting that overcoming CAF-imposed barriers to NK cytotoxicity and tumor infiltration is essential to unleash their anti-tumoral properties.
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BibTeX
@article{rodrigues2026cancerassociated,
title = {{Cancer-associated fibroblast subtypes differentially modulate natural killer cells in cancer}},
author = {Leonor Nunes Rodrigues and Hafsa Munir and Ibone Thate Arrazola and Matthias M. Gaida and Christoph Eckert and Jérôme Boulanger A and Ana C.F. Ferreira and Andrew N. J. McKenzie and Jacqueline D. Shields},
journal = {Cell Reports},
year = {2026},
month = jun,
doi = {10.1016/j.celrep.2026.117527},
url = {https://doi.org/10.1016/j.celrep.2026.117527},
note = {CC BY},
}
RIS
TY - JOUR
TI - Cancer-associated fibroblast subtypes differentially modulate natural killer cells in cancer
AU - Leonor Nunes Rodrigues
AU - Hafsa Munir
AU - Ibone Thate Arrazola
AU - Matthias M. Gaida
AU - Christoph Eckert
AU - Jérôme Boulanger A
AU - Ana C.F. Ferreira
AU - Andrew N. J. McKenzie
AU - Jacqueline D. Shields
PY - 2026
DA - 2026/06/01
JO - Cell Reports
DO - 10.1016/j.celrep.2026.117527
UR - https://doi.org/10.1016/j.celrep.2026.117527
AB - Natural killer (NK) cells are cytotoxic innate lymphoid cells which directly kill tumor cells, thus represent an attractive target for immunotherapy. However, NK cells face immunosuppression in the tumor microenvironment (TME), rendering them dysfunctional. While cancer-associated fibroblasts (CAFs) represent an abundant, heterogeneous component of pancreatic ductal adenocarcinoma (PDAC), their interplay with NK cells is largely understudied. Analyzing human samples and employing mouse models of PDAC and functional assays, we observed that intratumoral NK cells are immature, and TGF-β driven myofibroblastic (my)CAFs are strong NK suppressors, in contrast to inflammatory (i)CAF. Furthermore, myCAF-enriched tumor areas excluded NK cells, consistent with their reduced capacity to attract NK cells. Pancreatic CAFs in general reduced NK cell cytotoxicity by direct contact and via soluble factors, including prostaglandin E2 (PGE2). This work reveals distinct and overlapping roles of CAF subpopulations on NK cell functions, suggesting that overcoming CAF-imposed barriers to NK cytotoxicity and tumor infiltration is essential to unleash their anti-tumoral properties.
SN - 2211-1247
SN - 2639-1856
ER -