β-adrenergic signaling blockade attenuates metastasis through activation of cytotoxic CD4 T cells

Klaire Yixin Fjæstad, Astrid Zedlitz Johansen, Hannes Linder, Kevin James Baker, Milou Schattefor, Nadia Kolvig Czajkowski, Marie-Louise Thorseth, Majken Siersbæk, Annina Kurzay, Maria Perez-Penco, Anne Rahbech, Sara Fresnillo Saló, Lars Henning Engelholm, Inge Marie Svane, Mads Hald Andersen, Niels Junker, Lars Grøntved, Per thor Straten and Daniel Hargbøl Madsen ()
Additional contact information
Klaire Yixin Fjæstad: Copenhagen University Hospital - Herlev and Gentofte
Astrid Zedlitz Johansen: Copenhagen University Hospital - Herlev and Gentofte
Hannes Linder: Copenhagen University Hospital - Herlev and Gentofte
Kevin James Baker: Copenhagen University Hospital - Herlev and Gentofte
Milou Schattefor: Copenhagen University Hospital - Herlev and Gentofte
Nadia Kolvig Czajkowski: Copenhagen University Hospital - Herlev and Gentofte
Marie-Louise Thorseth: Copenhagen University Hospital - Herlev and Gentofte
Majken Siersbæk: University of Southern Denmark
Annina Kurzay: Copenhagen University Hospital - Herlev and Gentofte
Maria Perez-Penco: Copenhagen University Hospital - Herlev and Gentofte
Anne Rahbech: Copenhagen University Hospital - Herlev and Gentofte
Sara Fresnillo Saló: Copenhagen University Hospital - Herlev and Gentofte
Lars Henning Engelholm: University of Copenhagen
Inge Marie Svane: Copenhagen University Hospital - Herlev and Gentofte
Mads Hald Andersen: Copenhagen University Hospital - Herlev and Gentofte
Niels Junker: Copenhagen University Hospital - Herlev and Gentofte
Lars Grøntved: University of Southern Denmark
Per thor Straten: Copenhagen University Hospital - Herlev and Gentofte
Daniel Hargbøl Madsen: Copenhagen University Hospital - Herlev and Gentofte

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract β-adrenergic signaling has been suggested to promote tumor growth, and β-blockers are being evaluated for repurposing for cancer treatment. Here, we identify a β-adrenergic signaling axis involved in metastasis formation. We show that the β-blocker propranolol has strong anti-metastatic activity in multiple murine models, with this effect being completely dependent on CD4 + T cells and independent of NK or CD8 + T cells. We also observe that CD4 + T cells are required for the anti-tumor effect of propranolol in a syngeneic subcutaneous model of colon cancer. Mechanistically, propranolol induces a Th1-polarized and cytotoxic CD4 + T cell response, which requires MHC class II expression by cancer cells for full efficacy. We also report propanolol-driven systemic changes in the monocyte compartment, and upon depletion of monocytes, propranolol loses its anti-tumor effects. Finally, we show that propranolol treatment synergizes with anti-CTLA-4 therapy to further enhance CD4 + T cell infiltration and control metastasis. Thus, we show that β-adrenergic signaling limits CD4 T cell-mediated anti-tumor immunity, highlighting the potential of repurposing β-blockers for cancer treatment.

Date: 2025
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-65048-9 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-65048-9

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-65048-9

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().