ORIGINAL RESEARCH article
Front. Oncol.
Sec. Breast Cancer
Volume 15 - 2025 | doi: 10.3389/fonc.2025.1538574
This article is part of the Research TopicExploring the Breast Tumor Microenvironment: Association to Metastasis, Novel Risk Factors and Novel Treatments and Immunotherapies: Volume II.View all 8 articles
Resolving tumor microenvironment heterogeneity to forecast immunotherapy response in triple-negative breast cancer through multi-scale analysis
Provisionally accepted
- First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Background: Immunotherapy has been used in the clinical management of TNBC. While BRCA1 mutations are associated with immunotherapy response, the therapeutic outcomes in TNBC patients are not promising.This study integrated spatial, single-cell, and bulk RNA-seq data to explore the role of BRCA1 in reshaping the TNBC microenvironment. Through multi-scale analysis, phenotype changes and potential biomarkers in cancer-associated fibroblasts (CAF) were identified. To validate these findings at the protein level, we employed high-resolution, label-free proteomics sequencing in our in-house cohort, providing critical real-world validation. A predictive system for response to ICIs was constructed through the step-by-step machine learning pipeline.Results: Compared to BRCA1 mutant patients, BRCA1 wild-type patients experienced increased T-cell exhaustion and dendritic cell tolerance. We identified a MEG3+ pre-CAF subgroup via pseudo-time analysis. Moreover, ISG15 may serve as an immunoregulatory biomarker, and the proposed predictive model demonstrated potential in forecasting immunotherapy response, although further validation is needed.This study highlighted the cellular heterogeneity of TNBC and identified ISG15 as a candidate biomarker potentially associated with treatment response.The ISG15-based predictive system might provide a robust framework for predicting ICI response.
Keywords: Triple-negative breast cancer, BRCA1 mutation, Tumor Microenvironment, cancer-associated fibroblasts, Immune checkpoint inhibitor
Received: 03 Dec 2024; Accepted: 23 Jun 2025.
Copyright: © 2025 Sun, Chen, Li, Zhang, Wang, Sun, Xu, Chi, Wang and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Jiangrui Chi, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
Xinxing Wang, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
Lin Li, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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