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.

Background: Natural killer (NK) cells play crucial roles in mediating anti-cancer activity in breast cancer (BRCA). However, the potential of NK cell-related molecules in predicting BRCA outcomes and guiding personalized therapy remains largely unexplored. This study focused on developing a prognostic and therapeutic prediction model for BRCA by incorporating NK cell-related genes.Methods: The data analyzed primarily originated from the TCGA and GEO databases. The prognostic role of NK cells was evaluated, and marker genes of NK cells were identified via single-cell analysis. Module genes closely associated with immunotherapy resistance were identified by bulk transcriptome-based weighted correlation network analysis (WGCNA). Following taking intersection and LASSO regression, NK-related genes (NKRGs) relevant to BRCA prognosis were screened, and the NK-related prognostic signature was subsequently constructed. Analyses were further expanded to clinicopathological relevance, GSEA, tumor microenvironment (TME) analysis, immune function, immunotherapy responsiveness, and chemotherapeutics. Key NKRGs were screened by machine learning and validated by spatial transcriptomics (ST) and immunohistochemistry (IHC).Results: Tumor-infiltrating NK cells are a favorable prognostic factor in BRCA. By combining scRNA-seq and bulk transcriptomic analyses, we identified 7 NK-related prognostic NKRGs (CCL5, EFHD2, KLRB1, C1S, SOCS3, IRF1, and CCND2) and developed an NK-related risk scoring (NKRS) system. The prognostic reliability of NKRS was verified through survival and clinical relevance analyses across multiple cohorts. NKRS also demonstrated robust predictive power in various aspects, including TME landscape, immune functions, immunotherapy responses, and chemotherapeutic sensitivity. Additionally, KLRB1 and CCND2 emerged as key prognostic NKRGs identified through machine learning and external validation, with their expression correlation with NK cells confirmed in BRCA specimens by ST and IHC.Conclusions: We developed a novel NK-related gene signature that has proven valuable for evaluating prognosis and treatment response in BRCA, expecting to advance precision medicine of BRCA.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder driven by dysregulated immune responses. Macrophage-mediated inflammation is central to the pathology, and it is important to understand the epigenetic mechanisms involved. By screening epigenetic molecules that are differentially expressed in published human IBD datasets, we find Protein Arginine Methyltransferase 6 (PRMT6) consistently downregulated in IBD samples compared to healthy controls. Co-occurrence of Prmt6 suppression and Il1b induction within the myeloid compartment in colon biopsy samples indicates that PRMT6 limits macrophage-driven inflammation. Concordantly, Prmt6-deficient mice exhibit increased susceptibility to both DSS- and TNBS-induced colitis, characterized by exacerbated tissue damage and systemic elevation of IL-1β. Transcriptomic profiling confirms that PRMT6 deficiency selectively upregulates Il1b among inflammatory mediators. Mechanistically, PRMT6 suppresses Il1b transcription by interacting with RBBP5 and disrupting SET1A complex assembly, thereby reducing H3K4me3 enrichment at the Il1b promoter, independently of its canonical H3R2me2a catalytic activity. Furthermore, PRMT6 is transcriptionally silenced by the NF-κB subunit p50 during inflammation. Pharmacological inhibition of p50 restores PRMT6 expression, thus protecting mice from DSS-induced colitis in a PRMT6-dependent manner. Our findings highlight PRMT6 as a pivotal epigenetic regulator of the inflammatory response and provide proof of principle for targeting the p50–PRMT6–IL-1β axis in IBD.