The scale of neutrophil involvement in cancer is staggering. Neutrophils are the most numerous circulating leukocytes in humans, produced at a rate of roughly one hundred billion cells per day in the bone marrow, and they can constitute the dominant immune population within many solid tumors. Large-scale analyses of the tumor immune landscape across human cancers have repeatedly found that high intratumoral neutrophil content correlates with poor prognosis in numerous malignancies, including renal cell carcinoma, head and neck cancer and non-small cell lung cancer. The neutrophil-to-lymphocyte ratio, a simple blood measurement, has emerged as one of the most robust prognostic biomarkers in oncology, predicting outcomes across tumor types and even forecasting response to immune checkpoint inhibitors.

Why would the immune system’s first responders become cancer’s accomplices? The answer, the review argues, lies in the extraordinary plasticity of neutrophils and their exquisite sensitivity to environmental cues. Tumors are, in the words of a classic 1986 observation by Harold Dvorak, wounds that do not heal, and neutrophils are the cells that respond to wounds. Cancers exploit the same inflammatory programs that neutrophils deploy during tissue repair. Tumor-derived signals such as granulocyte colony-stimulating factor, transforming growth factor-beta, interleukin-8 and other chemokines reprogram both the production and the function of neutrophils, driving emergency granulopoiesis in the bone marrow and recruiting immature, immunosuppressive granulocytes into the circulation and the tumor bed.

Once inside the tumor microenvironment, neutrophils promote cancer through several mechanistically distinct pathways. They release vascular endothelial growth factor and, critically, matrix metalloproteinase-9, an enzyme that liberates sequestered VEGF from the extracellular matrix and triggers the angiogenic switch that transforms a dormant lesion into a growing tumor. Studies in mouse models of multistage carcinogenesis showed that infiltrating neutrophils mediate this initial angiogenic switch, and human neutrophils are unique in releasing MMP-9 free of its natural inhibitor TIMP-1, making it an especially potent driver of new blood vessel formation. Neutrophil elastase, another granule protease, can degrade insulin receptor substrate-1 in tumor cells to accelerate lung tumor growth, and myeloid cell-derived reactive oxygen species have been shown to induce mutagenesis in adjacent epithelial cells, directly fueling the genomic instability that drives malignant transformation.

Perhaps no neutrophil behavior has attracted more attention in recent years than the formation of neutrophil extracellular traps, or NETs. First described in 2004 as web-like structures of DNA, histones and granule proteins that ensnare bacteria, NETs have since been implicated in a remarkable range of tumor-promoting processes. Recent work published in Nature demonstrated that NETs drive vascular occlusion, tumor necrosis and metastasis, linking phenomena long thought to be independent. NETs can sequester circulating tumor cells, shielding them from cytotoxic lymphocytes and natural killer cells; NET-associated DNA can bind the receptor CCDC25 on cancer cells, directing their migration; and NETs produced during systemic inflammation can awaken dormant cancer cells, triggering metastatic relapse years after primary tumor removal. Strikingly, the metastatic spread of breast cancer has been shown to accelerate during sleep, when rhythmic fluctuations in circulating neutrophils and cancer cell dynamics converge.

Neutrophils also construct the pre-metastatic niche, the distant soil that primary tumors prepare to receive their disseminated seeds. Tumor-derived factors mobilize neutrophils and their progenitors to future metastatic sites, where they suppress natural killer cell activity, remodel the extracellular matrix and create an immunologically permissive environment. In breast cancer models, neutrophils support the lung colonization of metastasis-initiating cells, and chronic stress has been shown to increase metastasis through neutrophil-mediated changes to the microenvironment. Even glucocorticoids, widely used clinically, can promote breast cancer metastasis by acting on these cells. The circadian biology of neutrophils, governed by an intrinsic molecular timer that coordinates immune defense and vascular protection, adds another layer of complexity to how and when these cells enable metastatic spread.

Yet the story is emphatically not one-directional. The review devotes substantial attention to the antitumor capacities of neutrophils, which many of the same molecules can mediate depending on context. Neutrophil elastase, which promotes tumor growth in some settings, has been shown in other contexts to selectively kill cancer cells and attenuate tumorigenesis, with important differences between mouse and human neutrophils in the production of its inhibitor, secretory leukocyte proteinase inhibitor. Activated neutrophils exert direct cytotoxicity against melanoma cells through reactive oxygen species, and tumor-associated neutrophils in early-stage human lung cancer can stimulate T cell responses rather than suppress them. Tumor-entrained neutrophils have even been shown to inhibit metastatic seeding in the lung, providing early evidence of spontaneous antimetastatic function. The pro- versus antitumor polarization of neutrophils, famously framed as N1 versus N2 states, is now understood to reflect a continuum of environmentally determined functional states rather than fixed identities.

This dual nature is precisely what makes neutrophils such compelling therapeutic targets. The review highlights several promising strategies. Neutrophil-activating therapy, developed by the Stanford group, demonstrated that pharmacologically activated neutrophils can eradicate tumors and reduce metastases independently of adaptive immunity. CD40 agonist antibodies recruit a subset of neutrophils associated with tumor control, and T cell immunotherapies have been shown to engage neutrophils to eliminate antigen-escape variants that would otherwise survive checkpoint blockade. Bacille Calmette-Guerin, the century-old tuberculosis vaccine used to treat bladder cancer, works in part by reprogramming hematopoiesis so that neutrophils develop the capacity to attack tumor cells, and interferon-gamma induces NET formation with tumor-killing activity in colorectal cancer. On the inhibitory side, CXCR2 antagonists, peptidyl arginine deiminase 4 inhibitors that block NET formation, arginase inhibitors, and antibodies that block the NET-associated immunosuppressive enzyme arginase-1 are all in clinical development, several in combination with checkpoint inhibitors.

Antibody-based approaches represent another frontier. Neutrophils are extraordinarily potent mediators of antibody-dependent cellular cytotoxicity, and IgA antibodies in particular trigger superior neutrophil-mediated killing of cancer cells compared with conventional IgG, engaging the Fc-alpha receptor to produce vigorous respiratory bursts and trogoptosis, a process in which neutrophils progressively strip membrane fragments from antibody-coated targets. Combining IgA-based therapeutics with blockade of the CD47-SIRP-alpha innate immune checkpoint, which prevents phagocytosis, has shown enhanced neutrophil cytotoxicity against neuroblastoma and other malignancies. Even more ambitiously, researchers have engineered chimeric antigen receptor neutrophils derived from induced pluripotent stem cells, which possess potent activity against solid tumors and can serve as delivery vehicles for tumor-microenvironment-responsive nanodrugs in glioblastoma. Neutrophils bearing adhesive polymer micropatches have been proposed as a drug-free immunotherapy platform.

The authors caution that translating these findings into the clinic requires resolving fundamental questions about neutrophil heterogeneity, nomenclature and species differences. A consensus statement has established standards for myeloid-derived suppressor cell classification, and recent single-cell atlases have mapped neutrophil developmental trajectories across tissues and disease states, revealing that mature and immature neutrophils converge on similar transcriptional signatures within tumors. Human and mouse neutrophils differ in important ways, including their circadian rhythms, granule composition and lifespan, with human neutrophils surviving approximately five days rather than hours as once believed. Nevertheless, the convergence of mechanistic insight, biomarker validation and early clinical activity suggests that the field has reached an inflection point. Neutrophils, long dismissed as terminally differentiated foot soldiers, are now recognized as master regulators of the tumor ecosystem, and learning to command them, rather than simply deplete them, may define the next era of cancer immunotherapy.

Subject of Research: The roles of neutrophils in tumor progression, immunosuppression, metastasis and cancer therapy

Article Title: Neutrophils in cancer

Article References: Diehl, M. I., Basto, P. A., Abikenari, M. A., Linde, I. L., Okwan-Duodu, D., & Engleman, E. G. (2026). Neutrophils in cancer. Nature Reviews Cancer. https://doi.org/10.1038/s41568-026-00968-2

Image Credits: AI Generated

DOI: 10.1038/s41568-026-00968-2

Keywords: neutrophils, cancer, tumor microenvironment, neutrophil extracellular traps, metastasis, immunosuppression, angiogenesis, tumor-associated neutrophils, immunotherapy, myeloid-derived suppressor cells, NETosis, granulopoiesis