G-CSF/NAMPT signaling drives neutrophil dysfunction and enhances bacterial infection susceptibility in cancer patients

Despite advancements in cancer therapies, bacterial complications remain a major challenge, delaying treatment and worsening outcomes. While immunosuppressive therapies and prolonged hospitalizations contribute, they do not fully explain the elevated infection risk in cancer patients. Here we show that tumors producing high levels of granulocyte colony-stimulating factor (G-CSF) promote the persistence of Gram-negative pathogens in head and neck squamous cell carcinoma due to neutrophil reprogramming. Mechanistically, we identify tumor-driven activation of the G-CSF / nicotinamide phosphoribosyltransferase (NAMPT) signaling axis in neutrophil progenitors, resulting in impaired antibacterial functions, such as phagocytosis and neutrophil extracellular traps formation, and development of tissue-damaging neutrophil subsets. This disrupts lung tissue integrity and facilitates bacterial persistence. Importantly, targeting the G-CSF/NAMPT pathway prevents the generation of dysfunctional neutrophils and improves bacterial clearance in vivo. Our findings reveal tumor-induced, NAMPT-dependent neutrophil reprogramming as a central driver of compromised antimicrobial defenses in cancer. Therapeutic strategies aimed at modulating G-CSF/NAMPT signaling could enhance infection control and survival for cancer patients.

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Publication Details

Journal
Nature Communications
Published
2025-12-12
DOI
https://doi.org/10.1038/s41467-025-67471-4
Primary Topic
Neutrophil, Myeloperoxidase and Oxidative Mechanisms
Type
article
Field-Weighted Citation Impact
0.00
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article

G-CSF/NAMPT signaling drives neutrophil dysfunction and enhances bacterial infection susceptibility in cancer patients

Stefan Mattheis, Corinna Haist, Jan Kehrmann, Irem Ozel et al.
Nature Communications
Neutrophil, Myeloperoxidase and Oxidative Mechanisms
article

G-CSF/NAMPT signaling drives neutrophil dysfunction and enhances bacterial infection susceptibility in cancer patients

Stefan Mattheis, Corinna Haist, Jan Kehrmann, Irem Ozel, Stephan Lang, Hartmut Schlüter, Olga Shevchuk, Jadwiga Jabłońska, Bente Siebels, Nastassia Kabankova, Daniel Robert Engel, Hannah Voß, Jana Riedesel, Markus Sperandio, Ekaterina Pylaeva, Cornelius Kürten, Helmut Hanenberg, Ilona Thiel, Lea Tollrian
article en

Abstract

Despite advancements in cancer therapies, bacterial complications remain a major challenge, delaying treatment and worsening outcomes. While immunosuppressive therapies and prolonged hospitalizations contribute, they do not fully explain the elevated infection risk in cancer patients. Here we show that tumors producing high levels of granulocyte colony-stimulating factor (G-CSF) promote the persistence of Gram-negative pathogens in head and neck squamous cell carcinoma due to neutrophil reprogramming. Mechanistically, we identify tumor-driven activation of the G-CSF / nicotinamide phosphoribosyltransferase (NAMPT) signaling axis in neutrophil progenitors, resulting in impaired antibacterial functions, such as phagocytosis and neutrophil extracellular traps formation, and development of tissue-damaging neutrophil subsets. This disrupts lung tissue integrity and facilitates bacterial persistence. Importantly, targeting the G-CSF/NAMPT pathway prevents the generation of dysfunctional neutrophils and improves bacterial clearance in vivo. Our findings reveal tumor-induced, NAMPT-dependent neutrophil reprogramming as a central driver of compromised antimicrobial defenses in cancer. Therapeutic strategies aimed at modulating G-CSF/NAMPT signaling could enhance infection control and survival for cancer patients.

Nature CommunicationsVol. 16(1)
Universität Hamburg (DE), German Cancer Research Center (DE), University Medical Center Hamburg-Eppendorf (DE), Essen University Hospital (DE), West German Heart and Vascular Center Essen (DE), Deutsches Konsortium für Translationale Krebsforschung (DE), Heinrich Heine University Düsseldorf (DE), University of Duisburg-Essen (DE), Ludwig-Maximilians-Universität München (DE)
Openalex Percentile: Top 54%
Neutrophil, Myeloperoxidase and Oxidative Mechanisms
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