# Multi-omics analysis of NET+ TAN explains the immunosuppressive TME and prognosis value of malignant clinical characteristics in TNBC

## TL;DR

This study identifies NET+ TAN as a key driver of immune suppression in triple-negative breast cancer, offering new insights into prognosis and treatment resistance.

## Contribution

A novel six-gene signature from NET+ TAN is shown to have strong prognostic value for TNBC survival prediction.

## Key findings

- NET+ TAN promotes an immunosuppressive tumor microenvironment linked to poor TNBC prognosis.
- Single-cell analysis reveals NET+ TAN repolarizes T-cells toward immune-suppressive phenotypes.
- SLC24A4 is identified as a potential therapeutic target based on super-enhancer analysis.

## Abstract

•NET+ TAN identified as driver of immunosuppressive tumor microenvironment in TNBC, linked to poor prognosis and tumor progression.•A novel six-gene signature derived from NET+ TAN shows robust prognostic value across multiple cohorts, with high clinical utility for TNBC survival prediction.•Super-enhancer analysis reveals key transcriptional regulatory networks underlying NET+ TAN activity, highlighting SLC24A4 as a promising therapeutic target.•Single-cell analysis demonstrates NET+ TAN repolarizes T-cells toward immune-suppressive phenotypes, elucidating mechanisms of immunotherapy resistance.•Integrative multi-omics approach uncovers novel epigenetic and transcriptional regulatory mechanisms governing TNBC immune microenvironment remodeling.

NET+ TAN identified as driver of immunosuppressive tumor microenvironment in TNBC, linked to poor prognosis and tumor progression.

A novel six-gene signature derived from NET+ TAN shows robust prognostic value across multiple cohorts, with high clinical utility for TNBC survival prediction.

Super-enhancer analysis reveals key transcriptional regulatory networks underlying NET+ TAN activity, highlighting SLC24A4 as a promising therapeutic target.

Single-cell analysis demonstrates NET+ TAN repolarizes T-cells toward immune-suppressive phenotypes, elucidating mechanisms of immunotherapy resistance.

Integrative multi-omics approach uncovers novel epigenetic and transcriptional regulatory mechanisms governing TNBC immune microenvironment remodeling.

Triple-negative breast cancer (TNBC) continues to exhibit a poor response to both immunotherapy and endocrine therapy, primarily due to its complex genetic heterogeneity and tumor immune microenvironment (TIME). Neutrophil extracellular traps (NETs) are involved in neutrophil development and degranulation in treatment-resistant tumors, particularly TNBC and metastatic cases. Using a combination of single-cell RNA sequencing (scRNA-seq) datasets, bulk mRNA sequencing data from The Cancer Genome Atlas (TCGA) cohort, microarray data from the METABRIC and GEO databases, and epigenetic sequencing resources, we comprehensively investigated the functional characteristics and prognostic potential of NET-positive tumor-associated neutrophils (NET+ TAN) in TNBC. A six-gene panel derived from NET+ TAN has been identified as a reliable diagnostic biomarker for the survival of patients with TNBC and has been validated across several independent cohorts. Notably, our findings indicate that NET+ TAN facilitate T cell reprogramming in TNBC, thereby establishing a suppressive TIME and promoting tumor progression. This study provides a comprehensive perspective on the significance of NETs in patients with TNBC, with the aim of offering genetic and epigenetic insights into the mechanisms by which NETs may transition from cold to hot tumor phenotype, as well as valuable recommendations for therapeutic strategies.

Image, graphical abstract