Abstract
Neutrophils are among the most abundant immune cell types in the tumour microenvironment and have been associated with poor outcomes across multiple cancer types. Yet despite mounting evidence of their role in tumour progression, therapeutic strategies targeting neutrophils have only recently gained attention and remain limited in scope. This is probably due to the increasing number of distinct neutrophil subtypes identified in cancer and the limited understanding of the mechanisms by which these subsets influence tumour progression and immune evasion. In this Review, we discuss the spectrum of neutrophil subtypes — including those with antitumour activity — and their potential to polarize towards tumour-suppressive phenotypes. We explore the molecular pathways and effector functions by which neutrophils modulate cancer progression, with an emphasis on identifying tractable therapeutic targets. Finally, we examine emerging clinical trials aimed at modulating neutrophil lineages and consider their implications for patient outcomes.
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Acknowledgements
This work was supported by grants to A.M.H. from the NIH (nos. R01CA282465 and P50CA228944).
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Glossary
- Citrullination
-
A post-translational modification whereby the amino acid arginine is converted to a unique amino acid termed citrulline. In neutrophils, this process is catalysed by the enzyme peptidyl arginine deiminase-4 (PAD4).
- Cross-dressing
-
The ability of some antigen presenting cells to display an exogenous peptide/MHC complex originating from a neighbouring cell or extracellular vesicle.
- Engineered bioparticles
-
Heat-killed or chemically killed bacteria (such as S. aureus) that can be engineered to induce an inflammatory response.
- HLA-DR+ neutrophils
-
A subset of neutrophils that display the MHC class II cell surface marker, HLA-DR. This affords the ability of this neutrophil subset to present antigen in a similar fashion to macrophages and dendritic cells.
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Kwak, J.W., Houghton, A.M. Targeting neutrophils for cancer therapy. Nat Rev Drug Discov 24, 666–684 (2025). https://doi.org/10.1038/s41573-025-01210-8
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DOI: https://doi.org/10.1038/s41573-025-01210-8
