Identification and validation of synergistic drug strategies targeting macrophage polarization in triple-negative breast cancer via single-cell transcriptomics and deep learning
Triple-negative breast cancer (TNBC) presents therapeutic challenges due to its immunosuppressive tumor microenvironment (TME) and limited targeted options. Analyzing scRNA-seq data from 24 TNBC patients using integrated transcriptomics, machine-learning, and pseudo-time trajectory mapping, we devel...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-09-01
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| Series: | Translational Oncology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1936523325001883 |
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| author | Qi Qi Wenhao Yang Liang Li Yuheng Tang Yongzhi Chen Hui Wang Sun Yingjie Jialin Shi Samina Gul Wenru Tang Jianyu Pang Xiaoli Xie |
| author_facet | Qi Qi Wenhao Yang Liang Li Yuheng Tang Yongzhi Chen Hui Wang Sun Yingjie Jialin Shi Samina Gul Wenru Tang Jianyu Pang Xiaoli Xie |
| author_sort | Qi Qi |
| collection | DOAJ |
| description | Triple-negative breast cancer (TNBC) presents therapeutic challenges due to its immunosuppressive tumor microenvironment (TME) and limited targeted options. Analyzing scRNA-seq data from 24 TNBC patients using integrated transcriptomics, machine-learning, and pseudo-time trajectory mapping, we developed a macrophage differentiation-based classifier (MMDCSS) (CD93, CHI3L1, ZBTB20) with remarkable prognostic accuracy (C-index: 0.929, 3-year AUC: 0.907). Computational pharmacology identified finasteride as a ZBTB20 modulator (binding energy:7.7 kcal/mol) capable of reversing tumor-induced M2 macrophage polarization. Finasteride significantly enhanced doxorubicin efficacy ex vivo and in vivo by reprogramming the TME, reducing M2 macrophage infiltration while promoting an M1 phenotype. Mechanistically, finasteride upregulated ZBTB20, counteracting TNBC-mediated suppression of this M1-associated transcription factor. Our findings establish ZBTB20 as a key regulator of macrophage polarization in TNBC and introduce finasteride as a clinically viable agent to reverse TME immunosuppression. Targeting macrophage polarization via ZBTB20 modulation, particularly by repurposing finasteride, offers a promising therapeutic strategy for TNBC with immediate translational potential. |
| format | Article |
| id | doaj-art-e1b1c9998dcb4ae4afef1a8c78c0e342 |
| institution | Matheson Library |
| issn | 1936-5233 |
| language | English |
| publishDate | 2025-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Translational Oncology |
| spelling | doaj-art-e1b1c9998dcb4ae4afef1a8c78c0e3422025-06-28T05:29:52ZengElsevierTranslational Oncology1936-52332025-09-0159102457Identification and validation of synergistic drug strategies targeting macrophage polarization in triple-negative breast cancer via single-cell transcriptomics and deep learningQi Qi0Wenhao Yang1Liang Li2Yuheng Tang3Yongzhi Chen4Hui Wang5Sun Yingjie6Jialin Shi7Samina Gul8Wenru Tang9Jianyu Pang10Xiaoli Xie11Laboratory of Molecular Genetics of Aging & Tumor, Medicine School, Kunming University of Science and Technology, ChinaLaboratory of Molecular Genetics of Aging & Tumor, Medicine School, Kunming University of Science and Technology, ChinaLaboratory of Molecular Genetics of Aging & Tumor, Medicine School, Kunming University of Science and Technology, ChinaLaboratory of Molecular Genetics of Aging & Tumor, Medicine School, Kunming University of Science and Technology, ChinaLaboratory of Molecular Genetics of Aging & Tumor, Medicine School, Kunming University of Science and Technology, ChinaLaboratory of Molecular Genetics of Aging & Tumor, Medicine School, Kunming University of Science and Technology, ChinaLaboratory of Molecular Genetics of Aging & Tumor, Medicine School, Kunming University of Science and Technology, ChinaLaboratory of Molecular Genetics of Aging & Tumor, Medicine School, Kunming University of Science and Technology, ChinaLaboratory of Molecular Genetics of Aging & Tumor, Medicine School, Kunming University of Science and Technology, ChinaCorresponding author at: No. 727, Jingming South Road, Kunming, Yunnan, China.; Laboratory of Molecular Genetics of Aging & Tumor, Medicine School, Kunming University of Science and Technology, ChinaCorresponding authors at: No. 727, Jingming South Road, The Chinese University of Hong Kong, Shenzhen Futian Biomedical Innovation R&D Center, Shenzhen, China, Kunming, Yunnan, China.; Laboratory of Molecular Genetics of Aging & Tumor, Medicine School, Kunming University of Science and Technology, ChinaCorresponding authors at: No. 727, Jingming South Road, The Chinese University of Hong Kong, Shenzhen Futian Biomedical Innovation R&D Center, Shenzhen, China, Kunming, Yunnan, China.; Laboratory of Molecular Genetics of Aging & Tumor, Medicine School, Kunming University of Science and Technology, ChinaTriple-negative breast cancer (TNBC) presents therapeutic challenges due to its immunosuppressive tumor microenvironment (TME) and limited targeted options. Analyzing scRNA-seq data from 24 TNBC patients using integrated transcriptomics, machine-learning, and pseudo-time trajectory mapping, we developed a macrophage differentiation-based classifier (MMDCSS) (CD93, CHI3L1, ZBTB20) with remarkable prognostic accuracy (C-index: 0.929, 3-year AUC: 0.907). Computational pharmacology identified finasteride as a ZBTB20 modulator (binding energy:7.7 kcal/mol) capable of reversing tumor-induced M2 macrophage polarization. Finasteride significantly enhanced doxorubicin efficacy ex vivo and in vivo by reprogramming the TME, reducing M2 macrophage infiltration while promoting an M1 phenotype. Mechanistically, finasteride upregulated ZBTB20, counteracting TNBC-mediated suppression of this M1-associated transcription factor. Our findings establish ZBTB20 as a key regulator of macrophage polarization in TNBC and introduce finasteride as a clinically viable agent to reverse TME immunosuppression. Targeting macrophage polarization via ZBTB20 modulation, particularly by repurposing finasteride, offers a promising therapeutic strategy for TNBC with immediate translational potential.http://www.sciencedirect.com/science/article/pii/S1936523325001883Triple-negative breast cancerTumor microenvironmentMacrophage polarizationZBTB20Combination therapy |
| spellingShingle | Qi Qi Wenhao Yang Liang Li Yuheng Tang Yongzhi Chen Hui Wang Sun Yingjie Jialin Shi Samina Gul Wenru Tang Jianyu Pang Xiaoli Xie Identification and validation of synergistic drug strategies targeting macrophage polarization in triple-negative breast cancer via single-cell transcriptomics and deep learning Translational Oncology Triple-negative breast cancer Tumor microenvironment Macrophage polarization ZBTB20 Combination therapy |
| title | Identification and validation of synergistic drug strategies targeting macrophage polarization in triple-negative breast cancer via single-cell transcriptomics and deep learning |
| title_full | Identification and validation of synergistic drug strategies targeting macrophage polarization in triple-negative breast cancer via single-cell transcriptomics and deep learning |
| title_fullStr | Identification and validation of synergistic drug strategies targeting macrophage polarization in triple-negative breast cancer via single-cell transcriptomics and deep learning |
| title_full_unstemmed | Identification and validation of synergistic drug strategies targeting macrophage polarization in triple-negative breast cancer via single-cell transcriptomics and deep learning |
| title_short | Identification and validation of synergistic drug strategies targeting macrophage polarization in triple-negative breast cancer via single-cell transcriptomics and deep learning |
| title_sort | identification and validation of synergistic drug strategies targeting macrophage polarization in triple negative breast cancer via single cell transcriptomics and deep learning |
| topic | Triple-negative breast cancer Tumor microenvironment Macrophage polarization ZBTB20 Combination therapy |
| url | http://www.sciencedirect.com/science/article/pii/S1936523325001883 |
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