Neutrophil Traps Activate Inflammasomes in Triple-Negative Breast Cancer Cells

Breast cancer is the most common cancer globally, representing 11.7% of all cases and 24.5% of cancer types in women, leading to 685,000 deaths in 2020. It's classified into subtypes like Luminal A/B, HER2-positive, and Triple-Negative Breast Cancer (TNBC), which lacks hormone receptors and HER2 expression. While genetic factors contribute to 5-10%, environmental and lifestyle factors are predominant. Understanding the role of immune cells and inflammatory pathways in TNBC progression, specifically how Neutrophil Extracellular Traps (NETs) influence inflammasome activation in MDA-MB-231 cells, is a critical knowledge gap.

The study demonstrated that NETs significantly induce inflammasome activation in MDA-MB-231 breast cancer cells. Exposure to NETs led to a 2.8-fold increase in caspase-1 cleavage and a 43% increase in IL-1β secretion compared to untreated control cells. This activation was dose-dependent, with maximal effects observed at 50 µg/mL NETs. The most important finding was that NETs specifically triggered the NLRP3 inflammasome pathway, evidenced by a 2.5-fold upregulation of NLRP3 gene expression and robust ASC speck formation. Furthermore, blocking P2X7 receptors or TLR4 with specific inhibitors significantly reduced NET-induced inflammasome activation by 60% and 55%, respectively, suggesting critical receptor involvement in this process.