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The Role of Neutrophils in Tumor Progression and Metastasis
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The Role of Neutrophils in Tumor Progression and Metastasis

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Metastasis".

Deadline for manuscript submissions: 30 June 2026 | Viewed by 14902

Special Issue Editors

Dr. Rakesh K. Singh

E-Mail Website
Guest Editor
Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
Interests: chemokines; angiogenesis; metastasis
Dr. Leah M. Cook

E-Mail Website
Guest Editor
Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
Interests: metastasis; prostate; breast; neutrophils; bone

Special Issue Information

Dear Colleagues,

A growing body of evidence indicates that the interactions between neoplastic cells and inflammatory cells play an important role in tumor pathogenesis. These interactions are mediated by inflammatory cytokines and chemokines, leading to the recruitment of tumor-stromal-associated myeloid and endothelial cells that directly and indirectly promote tumor angiogenesis, progression, and metastasis.  Neutrophils—the most abundant white blood cells in the circulation system—constitute a significant part of the tumor microenvironment, playing major roles in inflammation and cancer, and are highly involved in progression and metastasis. Additionally, abundant data suggest that neutrophils could be considered as emerging targets for multiple cancer types. This Special Issue will focus on the most recent advances in tumor-associated neutrophil recruitment, activation, and functions within the tumor microenvironment, regulating the progression and metastasis as well as development of TAN-targeted therapeutics.

Dr. Rakesh K. Singh
Dr. Leah M. Cook
Guest Editors

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • neutrophils
  • innate immunity
  • tumor
  • microenvironment
  • metastasis
  • targeted therapeutics

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Published Papers (5 papers)

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Research

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12 pages, 1160 KB  
Article
The Prognostic Role of Different Blood Cell Count-to-Lymphocyte Ratios in Patients with Lung Cancer at Diagnosis
by Ourania Papaioannou, Oraianthi Fiste, Eva Theohari, Fotios Sampsonas, Foteinos-Ioannis Dimitrakopoulos, Angelos Koutras, Ioannis Gkiozos, Ioannis Vathiotis, Elias Kotteas and Argyrios Tzouvelekis
Cancers 2025, 17(23), 3879; https://doi.org/10.3390/cancers17233879 - 4 Dec 2025
Cited by 3 | Viewed by 1163
Abstract
Background: Lung cancer (LC) is a complex-to-treat disease and remains the leading cause of cancer-related mortality. Methods: Our aim was to investigate the prognostic role of neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and monocyte to lymphocyte ratio [...] Read more.
Background: Lung cancer (LC) is a complex-to-treat disease and remains the leading cause of cancer-related mortality. Methods: Our aim was to investigate the prognostic role of neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and monocyte to lymphocyte ratio (MLR) in patients with LC. In this retrospective study, examining the period between 1 June 2020 and 31 May 2024, we recorded consecutive patients who presented to the Department of Respiratory Medicine, University Hospital of Patras, Patras, Greece, and received a first diagnosis of LC. The primary outcome was mortality risk analysis based on NLR, PLR, and MLR at diagnosis. Secondary outcomes included associations of tumor, node, metastasis (TNM) staging, and smoking with NLR, PLR, and MLR at diagnosis. Results: We identified 353 patients with a first diagnosis of LC. The mean age ± SD at the time of diagnosis was 68.1 ± 9.1 years. Most patients were male (77.9%, n = 275) and current or ex-smokers (58.1%, n = 205, and 39.1%, n = 138, respectively). Histological diagnosis was non-small-cell lung cancer (NSCLC), small-cell lung cancer (SCLC), and not otherwise specified (NOS) in 67.1% (n = 237), 29.8% (n = 105), and 3.1% (n = 11) of patients, respectively. Adenocarcinoma NSCLC was more common (40.2%, n = 142) compared to squamous NSCLC (25.5%, n = 90). In 12.9% of patients, we identified EGFR, KRAS, ALK, or BRAF molecular driver mutations, while PD-L1 expression was positive in 20.7% of patients. The majority of enrolled patients presented with advanced stage IV LC at diagnosis (63.2%, n = 223). Kaplan–Meier curves showed that patients with higher than the median NLR and PLR at diagnosis were associated with significantly higher mortality risk compared to those with lower than the median [HR: 0.58, (95% CI: 0.42 to 0.81) p = 0.0009 and HR: 0.71, (95% CI: 0.53 to 0.95) p = 0.02, respectively], while no differences in mortality risk were observed between patients with higher versus lower than the median MLR [HR: 0.84, (95% CI: 0.63 to 1.12) p = 0.22]. With regard to secondary outcomes, no associations between higher versus lower than the median NLR, PLR, or MLR values and TNM staging [4.0 (95% CI: 4.0–4.0) vs. 4.0 (95% CI: 4.0–4.0), p = 0.95, 4.0 (95% CI: 4.0–4.0) vs. 4.0 (95% CI: 4.0–4.0), p = 0.09, 4.0 (95% CI: 4.0–4.0) vs. 4.0 (95% CI: 4.0–4.0), p = 0.4, respectively], as well as smoking status [70 (95% CI: 60–80) vs. 80 (95% CI: 60–80), p = 0.10, 70 (95% CI: 60–80) vs. 80 (95% CI: 60–80), p = 0.46, 80 (95% CI: 60–80) vs. 70 (95% CI: 60–80), p = 0.96, respectively] were reported. Conclusions: NLR and PLR could serve as reliable and clinician-friendly prognosticators of clinical outcomes in patients with LC. Further validation cohorts are sorely needed to prove this notion. Full article
(This article belongs to the Special Issue The Role of Neutrophils in Tumor Progression and Metastasis)
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16 pages, 3817 KB  
Article
Neutrophil Dynamics Contribute to Disease Progression and Poor Survival in Pancreatic Cancer
by Reegan Sturgeon, Paran Goel, Caitlin Molczyk, Ridhi Bhola, Paul M. Grandgenett, Michael A. Hollingsworth and Rakesh K. Singh
Cancers 2025, 17(21), 3541; https://doi.org/10.3390/cancers17213541 - 1 Nov 2025
Cited by 2 | Viewed by 1183
Abstract
Background: Tumor-promoting inflammation and immune evasion are hallmarks of cancer, contributing to the survival and proliferation of tumor cells. Infiltrating leukocytes and pro-inflammatory cytokines released into the tumor microenvironment (TME) often cause this inflammation and immune evasion. Neutrophils are leukocytes that contribute [...] Read more.
Background: Tumor-promoting inflammation and immune evasion are hallmarks of cancer, contributing to the survival and proliferation of tumor cells. Infiltrating leukocytes and pro-inflammatory cytokines released into the tumor microenvironment (TME) often cause this inflammation and immune evasion. Neutrophils are leukocytes that contribute to inflammation and have immunomodulatory functions. They are shown to have pro- or anti-tumorigenic roles contingent on cancer type. Methods: In this study, we examined the role of neutrophil recruitment in pancreatic cancer (PC) progression using patient samples and murine models. Results: We observed enhanced neutrophil infiltration and neutrophil extracellular trap (NET) formation, which were dependent on disease stage and tumor site. Our murine model studies showed that the infiltration of neutrophils and NETs was dependent on disease progression. Moreover, chemokine receptor CXCR2 and its ligands played a crucial role in neutrophil recruitment. The expression of CXCR2 and its ligands was associated with a worse prognosis for patients. Conclusions: Our data demonstrates that gemcitabine therapy enhances neutrophil recruitment and NET formation in PC. In addition, we observed altered neutrophil phenotypes in PC dependent on disease progression, suggesting a context-dependent immunomodulatory role. Together, our data demonstrate that CXCR2-driven neutrophil recruitment increases with PC progression, is enhanced by gemcitabine chemotherapy, promotes an immunosuppressive microenvironment, and is associated with poor patient survival. Full article
(This article belongs to the Special Issue The Role of Neutrophils in Tumor Progression and Metastasis)
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28 pages, 3132 KB  
Article
Neutrophils in Cancer: Phenotypic Heterogeneity Across Tumor Models and Significant Alteration of Splenic Neutrophil Phenotype in Lymphosarcoma RLS40 Model Following DNase I Treatment
by Khetam Sounbuli, Ludmila A. Alekseeva, Aleksandra V. Sen’kova, Oleg V. Markov, Innokenty A. Savin, Marina A. Zenkova and Nadezhda L. Mironova
Cancers 2025, 17(16), 2631; https://doi.org/10.3390/cancers17162631 - 12 Aug 2025
Cited by 1 | Viewed by 1933
Abstract
Background/Objectives: Neutrophils have recently gained significant attention due to their heterogeneity in tumor settings. Recent data showed neutrophil pro- and anti-tumor profiles during tumor progression. However, the concessive causes of neutrophil skewing toward one or another profile are not fully understood. Methods [...] Read more.
Background/Objectives: Neutrophils have recently gained significant attention due to their heterogeneity in tumor settings. Recent data showed neutrophil pro- and anti-tumor profiles during tumor progression. However, the concessive causes of neutrophil skewing toward one or another profile are not fully understood. Methods: In this study, using RT-qPCR, flowcytometry, and confocal microscopy, we investigated the phenotype of splenic neutrophils of mice bearing Lewis lung carcinoma LLC, RLS40 lymphosarcoma, and B16 melanoma. Results: Our data showed an immunosuppressive phenotype in the case of the LLC model with PD-L1 and IL10 expression. In the B16 model, minimal changes in the neutrophil phenotype were observed, regardless of tumor size. In the RLS40 model, the neutrophil phenotype was associated with the tumor growth rate, where, in aggressively progressed tumors (RLS40High), CCL17 was expressed, while, in mice with controlled tumor growth (RLS40Low), anti-tumor markers were expressed (FAS, ICAM-1, PD-L1). DNase I treatment significantly reduced tumor growth and metastasis in the RLS40 model but not in B16, enhanced the anti-tumor profile in RLS40 neutrophils, and tended to reduce NET formation induced by A23187. Conclusions: The phenotype of neutrophils from tumor-bearing mice is influenced by the tumor type and progression stage. DNase I had anti-tumor, antimetastatic, and immunostimulatory effects and significantly modified the neutrophil profile in the immunogenic model RLS40. Full article
(This article belongs to the Special Issue The Role of Neutrophils in Tumor Progression and Metastasis)
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Review

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28 pages, 1748 KB  
Review
Neutrophil Dynamics in Response to Cancer Therapies
by Huazhen Xu, Xiaojun Chen, Yuqing Lu, Nihao Sun, Karis E. Weisgerber, Manzhu Xu and Ren-Yuan Bai
Cancers 2025, 17(15), 2593; https://doi.org/10.3390/cancers17152593 - 7 Aug 2025
Cited by 5 | Viewed by 3376
Abstract
Neutrophils are increasingly recognized as key players in the tumor microenvironment (TME), displaying functional plasticity that enables them to either promote or inhibit cancer progression. Depending on environmental cues, tumor-associated neutrophils (TANs) may polarize toward antitumor “N1” or protumor “N2” phenotypes, exerting diverse [...] Read more.
Neutrophils are increasingly recognized as key players in the tumor microenvironment (TME), displaying functional plasticity that enables them to either promote or inhibit cancer progression. Depending on environmental cues, tumor-associated neutrophils (TANs) may polarize toward antitumor “N1” or protumor “N2” phenotypes, exerting diverse effects on tumor growth, metastasis, immune modulation, and treatment response. While previous studies have focused on the pathological roles of TANs in cancer, less attention has been given to how cancer therapies themselves influence the behavior of TANs. This review provides a comprehensive synthesis of current knowledge regarding the dynamics of TANs in response to major cancer treatment modalities, including chemotherapy, radiotherapy, cell-based immunotherapies, and oncolytic viral and bacterial therapies. We discuss how these therapies influence TAN recruitment, polarization, and effector functions within the TME, and highlight key molecular regulators involved. By consolidating mechanistic and translational insights, this review emphasizes the potential to therapeutically reprogram TANs to enhance treatment efficacy. A deeper understanding of context-dependent TAN roles will be essential for developing more effective, neutrophil-informed cancer therapies. Full article
(This article belongs to the Special Issue The Role of Neutrophils in Tumor Progression and Metastasis)
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33 pages, 10838 KB  
Review
Neutrophils and Neutrophil-Based Drug Delivery Systems in Anti-Cancer Therapy
by Hicham Wahnou, Riad El Kebbaj, Soufyane Hba, Zaynab Ouadghiri, Othman El Faqer, Aline Pinon, Bertrand Liagre, Youness Limami and Raphaël Emmanuel Duval
Cancers 2025, 17(7), 1232; https://doi.org/10.3390/cancers17071232 - 5 Apr 2025
Cited by 25 | Viewed by 6179
Abstract
Neutrophils, the most abundant white blood cells, play a dual role in cancer progression. While they can promote tumor growth, metastasis, and immune suppression, they also exhibit anti-tumorigenic properties by attacking cancer cells and enhancing immune responses. This review explores the complex interplay [...] Read more.
Neutrophils, the most abundant white blood cells, play a dual role in cancer progression. While they can promote tumor growth, metastasis, and immune suppression, they also exhibit anti-tumorigenic properties by attacking cancer cells and enhancing immune responses. This review explores the complex interplay between neutrophils and the tumor microenvironment (TME), highlighting their ability to switch between pro- and anti-tumor phenotypes based on external stimuli. Pro-tumorigenic neutrophils facilitate tumor growth through mechanisms such as neutrophil extracellular traps (NETs), secretion of pro-inflammatory cytokines, and immune evasion strategies. They contribute to angiogenesis, tumor invasion, and metastasis by releasing vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs). Conversely, anti-tumor neutrophils enhance cytotoxicity by generating reactive oxygen species (ROS), promoting antibody-dependent cell-mediated cytotoxicity (ADCC), and activating other immune cells such as cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Recent advances in neutrophil-based drug delivery systems have harnessed their tumor-homing capabilities to improve targeted therapy. Neutrophil-mimicking nanoparticles and membrane-coated drug carriers offer enhanced drug accumulation in tumors, reduced systemic toxicity, and improved therapeutic outcomes. Additionally, strategies to modulate neutrophil activity, such as inhibiting their immunosuppressive functions or reprogramming them towards an anti-tumor phenotype, are emerging as promising approaches in cancer immunotherapy. Understanding neutrophil plasticity and their interactions with the TME provides new avenues for therapeutic interventions. Targeting neutrophil-mediated mechanisms could enhance existing cancer treatments and lead to the development of novel immunotherapies, ultimately improving patient survival and clinical outcomes. Full article
(This article belongs to the Special Issue The Role of Neutrophils in Tumor Progression and Metastasis)
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