Tissue localization of natural killer cells dictates surveillance of lung metastasis
The lung is a common metastatic site for various cancer types. Successful immune surveillance of lung metastasis depends on Natural Killer (NK) cells, but the underlying mechanisms are elusive. Here, we show that the pulmonary vasculature recruits and maintains highly cytotoxic, differentiated CD11b<sup>high</sup> NK cells through the integrins Lymphocyte Function-associated Antigen 1 (LFA-1) and Very Late Antigen (VLA-4). These NK cells rapidly eradicate metastasizing tumor cells within the vasculature. However, after the initial clearing phase, differentiated pulmonary NK cells largely remain intravascular and fail to track extravasated tumor cells. In contrast, metastatic nodules are preferentially infiltrated with circulating, less differentiated CD27<sup>high</sup> NK cells. Within the metastatic lung, CD11b<sup>high</sup> NK cells undergo a rapid impairment of their migratory and cytotoxic features, while the intranodular CD27<sup>high</sup> subset transitions towards a transforming growth factor β (TGF-β)-driven state with limited persistence. Our findings demonstrate that the compartmentalization of NK cells is key for effective tumor cell surveillance in lung metastasis and suggests that TGF-β-resistant CD27<sup>high</sup> NK cells may offer a promising therapeutic avenue to enhance local anti-tumor activity.
Authors
- Tobias Wertheimer (ORCID: https://orcid.org/0000-0002-8480-7391)
- Caroline Mussak (ORCID: https://orcid.org/0000-0002-1448-1410)
- Marijne Vermeer (ORCID: https://orcid.org/0000-0001-5869-0532)
- Gioana Litscher
- Sònia Tugues (ORCID: https://orcid.org/0000-0003-1206-3386)
- Lothar C. Dieterich (ORCID: https://orcid.org/0000-0001-7908-5710)
- Colin Sparano (ORCID: https://orcid.org/0000-0003-0776-6896)
- Burkhard Becher (ORCID: https://orcid.org/0000-0002-1541-7867)
- Laura Ducimetière
- Nicolò Coianiz (ORCID: https://orcid.org/0000-0002-4357-0359)
- André Fonseca (ORCID: https://orcid.org/0000-0003-2657-7660)
- Maud Mayoux (ORCID: https://orcid.org/0000-0002-3700-3120)
- Lukas Rindlisbacher (ORCID: https://orcid.org/0000-0002-9408-1336)
- Philipp Häne (ORCID: https://orcid.org/0009-0007-5197-3338)
- Stanislav Dergun (ORCID: https://orcid.org/0009-0000-7201-9032)
Institutions
- University of Freiburg (DE)
- University of Mannheim (DE)
- University of Zurich (CH)
- Heidelberg University (DE)
- University Medical Center Freiburg (DE)
- University Hospital Heidelberg (DE)
- University Medical Centre Mannheim (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-10-27
- DOI
- https://doi.org/10.1038/s41467-025-64531-7
- Citations
- 2
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 1.59
Funders
- National Science Foundation
- Novartis Foundation
- Wilhelm Sander-Stiftung
- Institut National de la Santé et de la Recherche Médicale
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Centre National de la Recherche Scientifique
- Universität Zürich
- Vontobel-Stiftung
- Olga Mayenfisch Stiftung
- Swiss Cancer Research Foundation