Development and External Validation of an M2 Macrophage-Related Prognostic Signature in Breast Cancer Using Multi-Omics Data and Machine Learning.

Authors

Yang Liu, Ye Liu, Hongyan Wang, Ziyang Xiao, Xinyue Chang, Zitao Li, Sufen Guo

Published in

Breast cancer (Dove Medical Press). Volume 18. Pages 636369. Epub Oct 21, 2026.

Abstract

Tumor-associated macrophages (TAMs), particularly the M2-like phenotype, are central regulators of breast cancer progression; however, clinically applicable models capturing their functional heterogeneity and biological mechanisms remain limited.
We integrated single-cell RNA sequencing, spatial transcriptomics, and bulk RNA-seq data to construct an M2 macrophage-centered gene landscape. A machine learning framework based on 10-fold cross-validation was used to develop a prognostic signature in the TCGA-BRCA cohort (training set), with external validation in the independent GSE96058 cohort. Immune infiltration, genomic instability, pathway activity, and cell-cell communication were analyzed. KLF4 was examined in breast cancer cells and macrophages using qRT-PCR, Western blotting, siRNA-mediated knockdown, and a Transwell co-culture system.
We identified a 16-gene M2 macrophage-related signature (M2MMS) that stratified patients into subgroups with distinct survival outcomes in both cohorts. High-risk tumors showed M2 macrophage enrichment, an immunosuppressive microenvironment, elevated genomic instability, and activation of E2F and MYC proliferative programs. Cell-cell communication analysis identified MDK-NCL as a dominant tumor-TME signaling axis. KLF4 was upregulated in breast cancer cells and in macrophages after co-culture, and silencing KLF4 attenuated CD206 induction, indicating that KLF4 is functionally involved in tumor cell-induced M2-like polarization in vitro.
The M2MMS links M2 macrophage-driven immune remodeling to breast cancer prognosis and provides a basis for risk stratification and mechanistic investigation. KLF4 represents a regulatory node in tumor-macrophage interaction in vitro; its role in vivo and the clinical utility of the M2MMS require further validation.

PMID:
42928788
Bibliographic data and abstract were imported from PubMed on 26 Oct 2026.

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