Resolving tumor microenvironment heterogeneity to forecast immunotherapy response in triple-negative breast cancer through multi-scale analysis
BackgroundImmunotherapy 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.MethodsThis study integrated spatial, single-cell, and bulk RNA-seq data to explore the role of BRCA...
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Frontiers Media S.A.
2025-08-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2025.1538574/full |
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| author | Shihao Sun Shuang Chen Kaiyuan Li Ge Zhang Ge Zhang Ge Zhang Nan Wang Yijia Xu Xinxing Wang Jiangrui Chi Lin Li Yi Sun |
| author_facet | Shihao Sun Shuang Chen Kaiyuan Li Ge Zhang Ge Zhang Ge Zhang Nan Wang Yijia Xu Xinxing Wang Jiangrui Chi Lin Li Yi Sun |
| author_sort | Shihao Sun |
| collection | DOAJ |
| description | BackgroundImmunotherapy 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.MethodsThis 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.ResultsCompared 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.ConclusionsThis 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. |
| format | Article |
| id | doaj-art-60f1bdf921784bcbbfbe99c57c5ca891 |
| institution | Kabale University |
| issn | 2234-943X |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Oncology |
| spelling | doaj-art-60f1bdf921784bcbbfbe99c57c5ca8912025-08-20T04:03:22ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2025-08-011510.3389/fonc.2025.15385741538574Resolving tumor microenvironment heterogeneity to forecast immunotherapy response in triple-negative breast cancer through multi-scale analysisShihao Sun0Shuang Chen1Kaiyuan Li2Ge Zhang3Ge Zhang4Ge Zhang5Nan Wang6Yijia Xu7Xinxing Wang8Jiangrui Chi9Lin Li10Yi Sun11Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, ChinaCenter of Reproductive Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, ChinaDepartment of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, ChinaDepartment of Cardiology, Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, ChinaDepartment of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, ChinaDepartment of Cardiology, Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, ChinaDepartment of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, ChinaDepartment of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, ChinaDepartment of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, ChinaDepartment of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, ChinaDepartment of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, ChinaDepartment of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, ChinaBackgroundImmunotherapy 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.MethodsThis 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.ResultsCompared 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.ConclusionsThis 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.https://www.frontiersin.org/articles/10.3389/fonc.2025.1538574/fulltriple-negative breast cancerBRCA1 mutationtumor microenvironmentcancer-associated fibroblastsimmune checkpoint inhibitor |
| spellingShingle | Shihao Sun Shuang Chen Kaiyuan Li Ge Zhang Ge Zhang Ge Zhang Nan Wang Yijia Xu Xinxing Wang Jiangrui Chi Lin Li Yi Sun Resolving tumor microenvironment heterogeneity to forecast immunotherapy response in triple-negative breast cancer through multi-scale analysis Frontiers in Oncology triple-negative breast cancer BRCA1 mutation tumor microenvironment cancer-associated fibroblasts immune checkpoint inhibitor |
| title | Resolving tumor microenvironment heterogeneity to forecast immunotherapy response in triple-negative breast cancer through multi-scale analysis |
| title_full | Resolving tumor microenvironment heterogeneity to forecast immunotherapy response in triple-negative breast cancer through multi-scale analysis |
| title_fullStr | Resolving tumor microenvironment heterogeneity to forecast immunotherapy response in triple-negative breast cancer through multi-scale analysis |
| title_full_unstemmed | Resolving tumor microenvironment heterogeneity to forecast immunotherapy response in triple-negative breast cancer through multi-scale analysis |
| title_short | Resolving tumor microenvironment heterogeneity to forecast immunotherapy response in triple-negative breast cancer through multi-scale analysis |
| title_sort | resolving tumor microenvironment heterogeneity to forecast immunotherapy response in triple negative breast cancer through multi scale analysis |
| topic | triple-negative breast cancer BRCA1 mutation tumor microenvironment cancer-associated fibroblasts immune checkpoint inhibitor |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2025.1538574/full |
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