J Leukoc Biol. 2026 Jun 16:qiag079. doi: 10.1093/jleuko/qiag079. Online ahead of print.
ABSTRACT
Neutrophils, the most abundant innate immune cells, act as first responders in host defense via phagocytosis, degranulation, ROS production and Neutrophil Extracellular Traps (NETs) formation. Emerging evidence reveals that neutrophils are highly plastic and heterogeneous, acting as critical regulators in tumor biology. Tumor-derived CXCL8 and G-CSF drive emergency granulopoiesis, neutrophil recruitment and functional reprogramming, leading to immune suppression, angiogenesis, matrix remodeling, metastasis and therapy resistance. In specific contexts, neutrophils also exert anti-tumor effects by direct cytotoxicity, enhancing T-cell responses and restricting metastasis, displaying a dual role in cancer. Notably, anti-tumor neutrophils are rare in steady-state tumors but emerge during therapy-induced immune remodeling. Single-cell and spatial multi-omics have challenged the classical N1/N2 dichotomy. Tumor-associated neutrophils (TANs) and polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are now viewed as overlapping, dynamic populations along a functional continuum, shaped by maturation, metabolism, hypoxia and tissue niches. This review summarizes the dual roles of neutrophils in tumor progression, abnormal granulopoiesis, functional polarization, and revised concepts of TANs and PMN-MDSCs. We highlight NETosis, immune suppression, metabolic reprogramming and therapy resistance, and outline clinical translation including biomarkers (e.g., NLR) and therapeutic strategies. Current challenges and future directions are discussed, aiming to precisely target pro-tumor neutrophils while preserving host antimicrobial immunity.
PMID:42300977 | DOI:10.1093/jleuko/qiag079