Serpin A1 Cargo Within Tumour-Derived Extracellular Vesicles Supports Pro-Tumoural Bias of Neutrophils in Cancer.
10 affiliations
- 1Department of Otorhinolaryngology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
- 2Department of Dermatology and Allergy, LMU Hospital, Ludwig-Maximilians-University, Munich, Germany.
- 3German Cancer Consortium (DKTK) Partner Site Düsseldorf/Essen, Essen, Germany.
- 4Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Poland.
- 5Department of Pediatrics III, University Children's Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
- 6German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany.
- 7Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
- 8Exosome Research Lab (ERL), Department of Gastroenterology Hepatology and Transplantation Medicine, University of Duisburg-Essen, Essen, Germany.
- 9Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Mannheim, Medical Faculty Mannheim, University Heidelberg, Mannheim, Germany.
- 10Department of Radiology, Medical University of Gdansk, Gdańsk, Poland.
Abstract
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.
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BibTeX
@article{domnich2026serpin,
title = {{Serpin A1 Cargo Within Tumour-Derived Extracellular Vesicles Supports Pro-Tumoural Bias of Neutrophils in Cancer.}},
author = {Maksim Domnich and Ekaterina Pylaeva and Elena Siakaeva and Nastassia Kabankova and Agnieszka Bedzinska and Damian Sojka and Aneta Zebrowska and Marta Gawin and Maren Soldierer and Yaping Yu and Malwina Rist and Daniel Fochtman and Bernd Giebel and Iris Helfrich and Ilona Thiel and Basant Kumar Thakur and Cornelius H L Kürten and Helmut Hanenberg and Sonja Ludwig and Piotr Widlak and Stephan Lang and Monika Pietrowska and Jadwiga Jablonska},
journal = {Journal of extracellular vesicles},
year = {2026},
month = nov,
doi = {10.1002/jev2.70385},
url = {https://europepmc.org/article/MED/42969065},
note = {CC BY},
}
RIS
TY - JOUR
TI - Serpin A1 Cargo Within Tumour-Derived Extracellular Vesicles Supports Pro-Tumoural Bias of Neutrophils in Cancer.
AU - Maksim Domnich
AU - Ekaterina Pylaeva
AU - Elena Siakaeva
AU - Nastassia Kabankova
AU - Agnieszka Bedzinska
AU - Damian Sojka
AU - Aneta Zebrowska
AU - Marta Gawin
AU - Maren Soldierer
AU - Yaping Yu
AU - Malwina Rist
AU - Daniel Fochtman
AU - Bernd Giebel
AU - Iris Helfrich
AU - Ilona Thiel
AU - Basant Kumar Thakur
AU - Cornelius H L Kürten
AU - Helmut Hanenberg
AU - Sonja Ludwig
AU - Piotr Widlak
AU - Stephan Lang
AU - Monika Pietrowska
AU - Jadwiga Jablonska
PY - 2026
DA - 2026/11/01
JO - Journal of extracellular vesicles
DO - 10.1002/jev2.70385
UR - https://europepmc.org/article/MED/42969065
AB - 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.
SN - 2001-3078
ER -