Inflammatory signaling pathways in neutrophils: implications for breast cancer therapy.

Neutrophils, key components of the innate immune system, have emerged as pivotal players in the tumor microenvironment (TME), particularly in breast cancer. These versatile cells contribute to both pro-tumorigenic and anti-tumorigenic processes through inflammatory signaling pathways that influence tumor progression, immune evasion, and therapeutic responses. Their recruitment to the TME, mediated by chemokines such as CXCL1 and CXCL8, and their subsequent activation underscore their complex role in breast cancer biology. Neutrophil extracellular traps, cytokine secretion, and reactive oxygen species production further highlight their dualistic nature in cancer pathophysiology. Critical inflammatory signaling pathways, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), Janus kinase/signal transducer and activator of transcription (JAK/STAT), mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K)/AKT, regulate neutrophil activity in breast cancer. Dysregulation of these pathways can lead to the promotion of angiogenesis, immune suppression, and metastasis. For example, the NF-κB pathway fosters the secretion of pro-inflammatory cytokines, while JAK/STAT signaling drives the differentiation of tumor-associated neutrophils. The MAPK and PI3K/AKT pathways influence neutrophil survival and chemotactic responses, further enhancing their contribution to the tumor-supportive microenvironment. Understanding these mechanisms provides a framework for therapeutic intervention.