N1 and N2 neutrophil subtypes in breast cancer: functional implications and clinical perspectives: a narrative review

Breast cancer (BC) remains a leading cause of cancer-related deaths globally, with the tumor microenvironment (TME) playing a pivotal role in disease progression. Neutrophils, the most abundant white blood cells, have gained attention for their dualistic role in cancer immunity. Two major neutrophil subtypes, N1 and N2, have been identified, each exhibiting distinct functions in the TME. N1 neutrophils are typically associated with anti-tumor immunity, promoting tumor cell clearance through mechanisms such as reactive oxygen species production, cytokine release, and the activation of cytotoxic immune cells. In contrast, N2 neutrophils promote tumor progression, metastasis, and immune suppression by secreting pro-angiogenic factors and recruiting regulatory immune cells like Tregs and myeloid-derived suppressor cells. The polarization of neutrophils into N1 or N2 subtypes is regulated by the dynamic interactions within the TME, including cytokines, hypoxic conditions, and signals from tumor cells. In BC, factors such as IL-8, transforming growth factor-beta, and granulocyte-macrophage colony-stimulating factor drive N2 polarization, contributing to tumor evasion of immune surveillance. Conversely, pro-inflammatory signals can induce N1 polarization, which is often linked to favorable clinical outcomes. However, in aggressive breast cancer subtypes such as triple-negative breast cancer, the TME is more conducive to N2 polarization, resulting in poor prognosis and resistance to treatment.