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The heterogeneity of neutrophils in cancer and its implication for therapeutic targeting

Nature Immunology volume 26, pages 17–28 (2025)Cite this article

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Abstract

Neutrophils have a pivotal role in safeguarding the host against pathogens and facilitating tissue remodeling. They possess a large array of tools essential for executing these functions. Neutrophils have a critical role in cancer, where they are largely associated with negative clinical outcome and resistance to therapy. However, the specific role of neutrophils in cancer is complex and controversial, owing to their high functional diversity and acute sensitivity to the microenvironment. In this Perspective, we discuss the accumulated evidence that suggests that the functional diversity of neutrophils can be ascribed to two principal functional states, each with distinct characteristics: classically activated neutrophils and pathologically activated immunosuppressive myeloid-derived suppressor cells. We discuss how the antimicrobial factors in neutrophils can contribute to tumor progression and the fundamental mechanisms that govern the pathologically activated myeloid-derived suppressor cells. These functional states play divergent roles in cancer and thus require separate consideration in therapeutic targeting.

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Fig. 1: Alternative views of neutrophil heterogeneity in cancer.
Fig. 2: Functional heterogeneity of neutrophils in cancer.
Fig. 3: The effect of major antimicrobial factors of neutrophils on tumor progression.
Fig. 4: Therapeutic targeting of PMN-CAs and PMN-MDSCs.

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Acknowledgements

This work was supported by National Institute of Health grants R01CA266342 and R01CA272946 to Y.N.

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  1. These authors contributed equally: Evgeniy Eruslanov, Yulia Nefedova.

Authors and Affiliations

  1. Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Evgeniy Eruslanov

  2. Wistar Institute, Philadelphia, PA, USA

    Yulia Nefedova

  3. ICC, Early Oncology R&D, AstraZeneca, Gaithersburg, MD, USA

    Dmitry I. Gabrilovich

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  1. Evgeniy Eruslanov
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  2. Yulia Nefedova
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  3. Dmitry I. Gabrilovich
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E.E., Y.N. and D.I.G. wrote and edited manuscript.

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Correspondence to Dmitry I. Gabrilovich.

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D.I.G. is an employee and shareholder of AstraZeneca. E.E. and Y.N. declare no competing interests.

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Nature Immunology thanks Vassiliki Boussiotis and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Ioana Staicu, in collaboration with the Nature Immunology team.

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Eruslanov, E., Nefedova, Y. & Gabrilovich, D.I. The heterogeneity of neutrophils in cancer and its implication for therapeutic targeting. Nat Immunol 26, 17–28 (2025). https://doi.org/10.1038/s41590-024-02029-y

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