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An Immune Gene Signature Stratifies Breast Cancer Prognosis Through iCAF-Driven Immunosuppressive Microenvironment
Sibin Mei1, Chenhao Bai1, Huijuan Wang2
1Department of Gastroenterology, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.
Biomedicines
|December 30, 2025
Summary
A new 13-gene immune signature accurately predicts breast cancer survival by analyzing tumor immune microenvironments. This finding offers potential for targeted therapies, particularly those focusing on inflammatory cancer-associated fibroblasts (iCAFs).
Area of Science:
- Oncology
- Immunology
- Bioinformatics
Background:
- Breast cancer remains a leading cause of cancer mortality in women.
- Accurate prognostic tools are crucial for individualized risk stratification and treatment.
- The tumor immune microenvironment significantly influences cancer progression and patient outcomes.
Purpose of the Study:
- To develop and validate a novel gene signature for predicting breast cancer prognosis.
- To investigate the relationship between the gene signature and the tumor immune microenvironment.
- To identify potential therapeutic targets based on immune and cellular characteristics of tumors.
Main Methods:
- Transcriptomic data from The Cancer Genome Atlas (TCGA) and an independent cohort were analyzed.
- Differential gene expression, Cox regression, and Least Absolute Shrinkage and Selection Operator (LASSO) regression were used to construct a 13-gene prognostic signature.
- Tumor immune microenvironment and single-cell RNA sequencing data were integrated to explore biological underpinnings.
Main Results:
- The 13-gene signature robustly stratified patients into low- and high-risk groups with significantly different overall survival in both cohorts.
- Low-risk tumors showed an antitumor immune profile (CD8+ T cells, Tfh cells, M1 macrophages), while high-risk tumors had an immunosuppressive profile (regulatory T cells, M2 macrophages).
- High-risk tumors exhibited an expansion of malignant epithelial cells and inflammatory cancer-associated fibroblasts (iCAFs), with higher iCAF scores correlating with poorer survival.
Conclusions:
- A validated 13-gene immune signature provides significant prognostic value in breast cancer.
- The signature's utility is linked to distinct immune microenvironmental features, including iCAF infiltration.
- Targeting iCAFs presents a promising therapeutic strategy for improving outcomes in high-risk breast cancer patients.
