A Novel Tumor-Associated Neutrophil-Related Risk Signature Based on Single-Cell and Bulk RNA-Sequencing Analyses Predicts the Prognosis and Immune Landscape of Breast Cancer

Tumor-associated neutrophils (TANs) are increasingly recognized as contributors to cancer prognosis and therapeutics. However, TAN-related targets of breast cancer (BRCA) remain scarce. This study aimed to develop a novel TAN-associated risk signature (TANRS) of BRCA using single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing data. Eighty-six TAN-related genes (TANRGs) were derived from the intersection of TAN marker genes identified from scRNA-seq with modular genes identified by weighted gene co-expression network analysis (WGCNA). The TANRS consisting of nine TANRGs (TAGLN2, IGF2R, LAMP2, TBL1X, ASAP1, DENND5A, SNRK, BCL3, and CEBPD) was constructed using Cox regression and the least absolute shrinkage and selection operator (LASSO) regression. The TANRS efficiently predicted the survival prognosis and clinicopathological progression of patients across multiple cohorts. Significant differences in immune infiltration landscapes between TANRS groups were observed. Additionally, patients with high TANRS exhibited tumor immunosuppression, enhanced cancer hallmarks, and unfavorable therapeutic effects. Four promising compounds for treating high-TANRS BRCA were also presented. SNRK was identified as a key prognostic TANRG, and its expression profile and correlation with TANs were validated using immunohistochemical assays of BRCA samples and spatial transcriptomic sections. This novel TAN-based signature exhibited promising predictive capabilities, with the potential to contribute to personalized medicine for BRCA patients.