Decoding low-density neutrophils in breast and lung cancer: from bystanders to drivers.

Abstract

Neutrophils, once viewed as short-lived and functionally uniform antimicrobial cells, are now recognized as highly plastic immune regulators with context-dependent roles in cancer. Among circulating neutrophil subsets, low-density neutrophils have emerged as a clinically relevant population in oncology due to their distinct phenotypic, potent immunosuppressive activity, and strong association with disease progression. Low-density neutrophils are rare in healthy individuals but markedly expanded in patients with solid tumors. Low-density neutrophils display enhanced activation, increased expression of immunoregulatory molecules such as programmed death-ligand 1, elevated reactive oxygen species production, and a heightened propensity for neutrophil extracellular trap formation, collectively impairing cytotoxic T cell function and promoting tumor immune evasion. Although low-density neutrophils have been described across multiple malignancies, their biological and clinical relevance has been most characterized in breast and lung cancers. This review synthesizes current knowledge on neutrophil biology, emphasizing the clinical and mechanistic features of low-density neutrophils, with a focus on these 2 tumor types. In breast cancer, increased low-density neutrophil abundance correlates with metastatic disease, poor response to neoadjuvant chemotherapy, immunosuppression, accelerated progression, and reduced survival. In lung cancer, elevated low-density neutrophil frequencies similarly associate with advanced disease stage, unfavorable clinical outcomes, and distinct surface marker profiles distinguishing them from high-density neutrophils. Mechanistic studies indicate that tumor-derived cytokines and chronic inflammation drive low-density neutrophil expansion, functional reprogramming, and tissue trafficking, linking systemic neutrophil dysregulation to advanced disease and metastatic progression. Finally, we highlight emerging biomarkers, unresolved challenges, and therapeutic strategies targeting neutrophil plasticity and low-density neutrophil-mediated immunosuppression, underscoring their potential as actionable components in precision oncology.