image: Potential pro- and anti-tumor functions of tumor-associated neutrophils (TANs). TANs may either promote or inhibit tumorigenesis and tumor progression through various immune mechanisms. (Figure left) Anti-tumor roles of TANs, which involve direct tumor cytotoxicity through secretion of protease granules, like reactive oxygen species (ROS) and myeloperoxidase (MPO). Additionally, TANs mediate the antibody-dependent cell-mediated cytotoxicity (ADCC) effect, facilitated by Fc receptors (FcR) on the surfaces, then activate and recruit other immune effector cells, leading to the elimination of antibody-targeted tumor cells by TANs. Apart from ADCC, TANs can further enhance the immune response. Dendritic cells, macrophages, and T cells secrete reactive cytokines within the TME, such as IL-12, TNF-α, and GM-CSF, which induce proliferation, maturation, and migration of TANs. TANs sequentially secrete C-C motif chemokine ligand 3 (CCL3), C-X-C motif chemokine ligand 9 (CXCL9), and CXCL10 that attract and recruit T cells, especially Th1 suppressing tumors to the TME. This coordinated action between TANs and other immune cells via cytokines and chemokines enhances the anti-tumor immune response. Overall, this dynamic interaction occurs predominantly in the early stage and is marked by a shorter cell lifespan and higher cell density. (Figure right) Pro-tumor roles of TANs in different aspects. TANs release abundant vascular endothelial growth factor-α (VEGF-α) and matrix metalloproteinase 9 (MMP-9), promoting angiogenesis and an increased blood supply, and a boost of tumor growth. In addition, enzymes, like elastases, MMP-8, MMP-9, cathepsin G, and proteinas-3 secreted by TANs, degrade the extracellular matrix and physical barrier facilitating tumor cell invasion into surrounding tissue. Moreover, TANs have an important role in promoting tumor proliferation in the late stage via secretion of neutrophil elastase (NE). Similarly, TANs have a negative effect on the immune system. Tumor necrosis factor-α (TNF-α), nitric oxide (NO), and arginase 1 (Arg-1) secreted by TANs and macrophage-1 Ag (Mac-1) and PD-L1 expressed on TANs suppress the immune response and enable tumors to escape the immune surveillance. CCL17 and CCL2 separately attract immune suppressive cells, like Tregs and myeloid-derived suppressor cells (MDSCs), leading to a favorably immune-deficient niche for tumors. In summary, TANs can also impair the anti-tumor immunity with a longer lifespan but lower cell density in the later stage of tumor progression. Notably, neutrophils in the TME can be transformed from pro-tumor phenotypes to anti-tumor phenotypes by IFN-β, IFN-γ, and retinoic acid. Reverse action can be achieved through TNF-α, tumor growth factor-β (TGF-β), IL-6, G-CSF, and IL-35, whereas IL-17 has a dual effect, in which subtle concentration changes influence the dynamic shift of neutrophils. ADCC, antibody-dependent cell-mediated cytotoxicity; Arg-1, arginase 1; CCL3, C-C motif chemokine ligand 3; CXCL9, C-X-C motif chemokine ligand 9; Mac-1, macrophage-1 Ag; MDSCs, myeloid-derived suppressor cells; MMP-9, matrix metalloproteinase 9; MPO, myeloperoxidase; NE, neutrophil elastase; NO, nitric oxide; ROS, reactive oxygen species; TANs, tumor-associated neutrophils; TNF-α, tumor necrosis factor-α; TGF-β, tumor growth factor-β; VEGF-α, vascular endothelial growth factor-α.
Credit: Cancer Biology & Medicine
Neutrophils, once considered simple foot soldiers of innate immunity, are now recognized as complex players in cancer. This review highlights how these cells, which typically defend the body from infection, can paradoxically support tumor progression through promoting angiogenesis, immune suppression, and metastasis. Yet, they also possess tumor-fighting capabilities under certain conditions. The dual nature of tumor-associated neutrophils (TANs)—either aiding or attacking cancer—depends on various signals within the tumor microenvironment. Understanding this plasticity opens doors to novel therapeutic strategies that can suppress their tumor-promoting roles while enhancing their anti-tumor potential.
Neutrophils are the most abundant type of white blood cells, critical for immune defense and inflammation control. Traditionally, their role in cancer was seen as minor, but emerging evidence reveals that neutrophils are deeply involved in all stages of tumor development. They can promote tumor growth, facilitate metastasis, and suppress the immune system—yet also mediate direct tumor cell killing and support T cell responses. This complexity stems from their ability to adopt distinct functional states influenced by the tumor microenvironment, cytokines, and systemic factors. Due to these challenges, there is a need for in-depth research on how to harness neutrophil plasticity for cancer therapy.
A new review (DOI: 10.20892/j.issn.2095-3941.2025.0023) published in Cancer Biology & Medicine by researchers from Zhejiang University and Wenzhou Medical University, comprehensively examines the multifaceted role of neutrophils in cancer. The authors explore how tumor-associated neutrophils (TANs) can be reprogrammed by their environment to either support or suppress tumor growth. By mapping the mechanisms of neutrophil polarization, chemotaxis, and interactions with tumor and immune cells, the study sheds light on promising therapeutic targets for cancer treatment.
The review outlines how neutrophils can be polarized into either anti-tumor (N1) or pro-tumor (N2) states. Tumor-derived signals like TGF-β, IL-6, and granulocyte-CSF (G-CSF) push neutrophils toward the N2 state, which enhances angiogenesis, suppresses cytotoxic T cells, and promotes metastasis. In contrast, cytokines like IFN-β and retinoic acid can induce the N1 phenotype, boosting immune surveillance and direct tumor cell killing. Neutrophils also engage in antibody-dependent cytotoxicity and can act as antigen-presenting cells under specific conditions. However, their role in metastasis is particularly complex—helping cancer cells survive in circulation, seed distant organs, and establish pre-metastatic niches. Therapies targeting neutrophil recruitment, such as CXCR2 and c-MET inhibitors, as well as strategies reprogramming TANs via STAT3 or TGF-β blockade, show potential in preclinical and early clinical studies. The short lifespan and plasticity of neutrophils, however, pose substantial challenges for therapeutic manipulation.
"Neutrophils are no longer seen as mere bystanders in cancer. Their dual nature makes them both a challenge and an opportunity in cancer therapy," said Dr. Chenghui Yang, corresponding author of the study. "Our review emphasizes the urgent need to better understand the factors driving neutrophil polarization. Future therapies will likely focus on re-educating these cells to tip the balance in favor of tumor suppression."
This review sets the stage for designing neutrophil-targeted therapies in oncology. By selectively inhibiting tumor-promoting neutrophils or reprogramming them into anti-tumor phenotypes, researchers hope to boost the effectiveness of immunotherapies. Drug strategies involving TGF-β inhibitors, CXCR2 antagonists, or nanoparticle-based delivery systems are already in early-phase trials. Additionally, blocking neutrophil-mediated pre-metastatic niche formation may help prevent cancer recurrence. As researchers continue to decode neutrophil behavior across different cancers and tumor stages, personalized immune interventions leveraging these "double agents" of immunity may soon become a cornerstone of precision oncology.
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References
DOI
10.20892/j.issn.2095-3941.2025.0023
Original Source URL
https://doi.org/10.20892/j.issn.2095-3941.2025.0023
Funding information
This work was supported by grants from the National Natural Science Foundation of China (Grant Nos. 82273449 and 82203663), the Zhejiang Provincial Natural Science Foundation of China (Grant No. LQ23H160013), and the Medical and Health Science and Technology Project of Zhejiang Province (Grant Nos. 2024KY1039 and 2024KY1250).
About Cancer Biology & Medicine
Cancer Biology & Medicine (CBM) is a peer-reviewed open-access journal sponsored by China Anti-cancer Association (CACA) and Tianjin Medical University Cancer Institute & Hospital. The journal monthly provides innovative and significant information on biological basis of cancer, cancer microenvironment, translational cancer research, and all aspects of clinical cancer research. The journal also publishes significant perspectives on indigenous cancer types in China. The journal is indexed in SCOPUS, MEDLINE and SCI (IF 8.4, 5-year IF 6.7), with all full texts freely visible to clinicians and researchers all over the world.
Journal
Cancer Biology & Medicine
Subject of Research
Not applicable
Article Title
Neutrophils in cancer: from immune defense to tumor promotion
Article Publication Date
2-Jul-2025
COI Statement
The authors declare that they have no competing interests.