N2 Neutrophils and Tumor Progression in Breast Cancer: Molecular Pathways and Implications.

Abstract

Neutrophils, traditionally viewed as first-line defenders in innate immunity, are increasingly recognized for their dualistic roles in cancer. In breast cancer, a distinct subset known as N2 neutrophils exhibits pro-tumorigenic activity, facilitating angiogenesis, immune suppression, and metastasis. This narrative review synthesizes current evidence on the molecular mechanisms underlying N2 polarization-focusing on key pathways such as TGF-β, STAT3/6, and hypoxia-mediated signaling-and their implications in breast cancer progression. We further explore how N2 neutrophils interact with other immune cells within the tumor microenvironment to promote an immunosuppressive milieu. A unique contribution of this review lies in its integration of emerging single-cell and flow cytometry data to underscore neutrophil plasticity and subtype-specific differences in neutrophil activity across breast cancer variants. Therapeutic strategies targeting N2 neutrophils are critically examined, including small-molecule inhibitors, cytokine blockade, and neutrophil-targeted nanomedicine. However, major challenges persist-most notably the difficulty in selectively depleting or reprogramming N2 neutrophils without compromising essential antimicrobial functions. Additionally, the lack of validated N2-specific markers in clinical samples limits translational progress. Addressing these gaps is crucial for the development of safe, effective immunomodulatory therapies in breast cancer.