Serpin A1 Cargo Within Tumour‐Derived Extracellular Vesicles Supports Pro‐Tumoural Bias of Neutrophils in Cancer
Tumour-derived extracellular vesicles (EVs) or exosomes are critical mediators of the cancer-immune system crosstalk, yet the mechanisms by which they reprogram neutrophil function in vivo remain insufficiently characterised. Here, we identify the serine protease inhibitor Serpin A1 as a predominant cargo component of small EVs (sEVs) released by head and neck cancer cels (HNC) and show that this molecule is both necessary and sufficient to confer a stable pro-tumoural programming of neutrophils. Uptake of Serpin A1-enriched sEVs elicits extensive proteomic remodelling in neutrophils including activation of STAT3 signalling, leading to sustained induction of PD-L1, increased Arginase 1 production and prolonged neutrophil lifespan. Functionally, these reprogrammed neutrophils acquire a capacity to drive epithelial-mesenchymal transition in tumour cells, and to impose exhaustion of T cells via metabolic restriction and arginine depletion, leading to their reduced cytotoxicity. Genetic ablation of Serpin A1 from tumour-derived sEVs or pharmacologic inhibition of serpin-STAT3 axis restores neutrophil anti-tumour functions. Collectively, these findings delineate a Serpin A1-STAT3/Arginase 1 as an important signalling pathway through which tumour-derived sEVs promote neutrophil-dependent immune suppression and tumour progression, and highlight EV-associated serpins as potential targets for future therapeutic intervention in cancer.
Authors
- Agnieszka Będzińska (ORCID: https://orcid.org/0000-0001-8795-2298)
- Malwina Rist
- Sonja Ludwig (ORCID: https://orcid.org/0000-0001-9751-323X)
- Helmut Hanenberg (ORCID: https://orcid.org/0000-0003-0451-2735)
- Aneta Zebrowska (ORCID: https://orcid.org/0000-0001-6049-301X)
- Stephan Lang (ORCID: https://orcid.org/0009-0000-4420-9664)
- Bernd Giebel (ORCID: https://orcid.org/0000-0003-2446-948X)
- Iris Helfrich (ORCID: https://orcid.org/0000-0001-6150-9570)
- Maren Soldierer (ORCID: https://orcid.org/0009-0002-7021-3143)
- Monika Pietrowska (ORCID: https://orcid.org/0000-0001-9317-7822)
- Daniel Fochtman (ORCID: https://orcid.org/0000-0002-0754-7012)
- Marta Gawin (ORCID: https://orcid.org/0000-0002-2834-5129)
- Yu Yaping
- Jadwiga Jabłońska (ORCID: https://orcid.org/0000-0003-1490-2542)
- Damian Robert Sojka (ORCID: https://orcid.org/0000-0003-1007-804X)
- Elena Siakaeva (ORCID: https://orcid.org/0000-0002-5607-2033)
- Nastassia Kabankova (ORCID: https://orcid.org/0000-0003-1506-4923)
- Maksim Domnich (ORCID: https://orcid.org/0000-0003-4954-5418)
- Basant Kumar Thakur (ORCID: https://orcid.org/0000-0001-7013-7895)
- Ekaterina Pylaeva (ORCID: https://orcid.org/0000-0002-3941-9664)
- Cornelius H. L. Kürten (ORCID: https://orcid.org/0000-0002-2720-0075)
- Ilona Thiel
- Piotr Widłak (ORCID: https://orcid.org/0000-0001-5099-4726)
Institutions
- Heidelberg University (DE)
- LMU Klinikum (DE)
- Essen University Hospital (DE)
- The Maria Sklodowska-Curie National Research Institute of Oncology (PL)
- Medizinische Fakultät Mannheim (DE)
- Deutsches Konsortium für Translationale Krebsforschung (DE)
- University of Duisburg-Essen (DE)
- Gdańsk Medical University (PL)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- Journal of Extracellular Vesicles
- Published
- 2026-11-01
- DOI
- https://doi.org/10.1002/jev2.70385
- Citations
- 1
- Primary Topic
- Extracellular vesicles in disease
- Type
- article
- Field-Weighted Citation Impact
- 0.00