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. 2024 May 18;23:107. doi: 10.1186/s12943-024-02004-z

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© The Author(s) 2024

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

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Fig. 1 — The development, mobilization, and clearance of neutrophils in the tumor microenvironment. Hematopoietic progenitor stem cells (HSCs) in the bone marrow differentiate into common myeloid progenitor cells (CMPs), which give rise to granulocyte-monocyte progenitor cells (GMPs) and eventually mature segmented neutrophils. Tumor-derived mediators such as granulocyte colony-stimulating factor (G-CSF) and S100 calcium-binding protein A9 (S100A9) promote the differentiation of the neutrophil and monocyte lineages while leading to systemic dendritic cell deficiency in vivo. Chemokines trigger the mobilization of mature and immature neutrophils into the circulation. Immature neutrophils, known as polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), are considered in this context. During transendothelial migration, the interaction between integrin α9β1 on neutrophils and vascular cell adhesion molecule 1 (VCAM-1) on endothelial cells stimulates the release of granulocyte-macrophage colony-stimulating factor (GM-CSF) from the latter, prolonging neutrophil lifespan. Neutrophils that extravasate into the tumor tissue adopt antitumor (type N1) or protumor (type N2) phenotypes, influenced by growth factor-β (TGF-β) and type 1 interferon (IFN), respectively. After fulfilling their functions, neutrophils undergo senescence due to intrinsic programs (CXCR2 or CXCR4) and extrinsic factors (microbiota) and are subsequently cleared by macrophages in the bone marrow, spleen, liver, and lungs. Neutrophils also undergo programmed death to form neutrophil extracellular traps (NETs)