{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T12:06:00Z","timestamp":1787313960500,"version":"build-2736575974"},"reference-count":31,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T00:00:00Z","timestamp":1767139200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002403","name":"Taibah University","doi-asserted-by":"crossref","award":["447-16-1060"],"award-info":[{"award-number":["447-16-1060"]}],"id":[{"id":"10.13039\/501100002403","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: Triple-negative breast cancer (TNBC) exhibits high immune infiltration yet remains clinically aggressive. Although immune checkpoint blockade benefits a subset of patients, the molecular programs enabling concurrent immune activation and immune evasion in TNBC are not fully defined. This study aimed to identify TNBC-specific tumor-intrinsic and tumor-extrinsic molecular features that may explain this paradox. Methods: Publicly available single-cell RNA-sequencing data from primary breast tumors were analyzed to characterize subtype-specific transcriptional programs across epithelial and stromal compartments. Tumor-intrinsic findings were independently validated using bulk transcriptomic and clinical data from the METABRIC cohort. Tumor microenvironment remodeling was evaluated using multiplexed tissue imaging of TNBC tumors. Functional analyses were done included Gene Ontology enrichment, Hallmark gene set enrichment analysis, and SERPINB3-centered protein\u2013protein interaction network analysis using STRING. Results: Single-cell analysis identified SERPINB3 as a TNBC-enriched epithelial gene relative to ER+ and HER2+ tumors. This subtype-restricted pattern was validated in the METABRIC cohort and associated with pathways related to epithelial\u2013mesenchymal transition, interferon signaling, and antigen presentation. TNBC tumors also displayed a humoral immune signature characterized by B-cell and plasmablast enrichment, as well as ectopic immunoglobulin gene expression in cancer-associated fibroblasts, endothelial cells, and myeloid populations. Multiplex imaging revealed coordinated associations between immune suppression, stromal activation, and tumor proliferation. Network analysis placed SERPINB3 within interconnected immune-regulatory and stromal signaling modules. Conclusions: Together, these data indicate that TNBC exhibits co-existing immune activation and immune-suppressive features. The identified epithelial and stromal signatures represent candidate biomarkers that may inform future studies of immune regulation and therapeutic stratification in TNBC.<\/jats:p>","DOI":"10.3390\/genes17010038","type":"journal-article","created":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T15:30:32Z","timestamp":1767195032000},"page":"38","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Multi-Modal Profiling Reveals SERPINB3-Driven Immune Evasion and Stromal Immune Mimicry in Triple-Negative Breast Cancer"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2952-9840","authenticated-orcid":false,"given":"Zinab O.","family":"Doha","sequence":"first","affiliation":[{"name":"Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taibah University, Madinah 42353, Saudi Arabia"},{"name":"Health and Life Research Center, Taibah University, Madinah 42353, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1634\/theoncologist.2010-S5-49","article-title":"Directed Therapy of Subtypes of Triple-Negative Breast Cancer","volume":"15","author":"Carey","year":"2010","journal-title":"Oncologist"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1038\/nrclinonc.2016.66","article-title":"Triple-negative breast cancer: Challenges and opportunities of a heterogeneous disease","volume":"13","author":"Bianchini","year":"2016","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2750","DOI":"10.1172\/JCI45014","article-title":"Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies","volume":"121","author":"Lehmann","year":"2011","journal-title":"J. Clin. Investig."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2108","DOI":"10.1056\/NEJMoa1809615","article-title":"Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer","volume":"379","author":"Schmid","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1354","DOI":"10.1001\/jamaoncol.2016.1061","article-title":"Variation in the Incidence and Magnitude of Tumor-Infiltrating Lymphocytes in Breast Cancer Subtypes: A Systematic Review","volume":"2","author":"Stanton","year":"2016","journal-title":"JAMA Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1038\/s41419-025-07873-w","article-title":"Molecular features of TNBC govern heterogeneity in the response to radiation and autophagy inhibition","volume":"16","author":"Fischer","year":"2025","journal-title":"Cell Death Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1314","DOI":"10.1186\/s12967-025-07370-w","article-title":"Recent progress in immune evasion mechanisms of triple-negative breast cancer","volume":"23","author":"Yang","year":"2025","journal-title":"J. Transl. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.cancergen.2025.03.004","article-title":"Identification of new immune target and signaling for cancer immunotherapy","volume":"294\u2013295","author":"Narote","year":"2025","journal-title":"Cancer Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1334","DOI":"10.1038\/s41588-021-00911-1","article-title":"A single-cell and spatially resolved atlas of human breast cancers","volume":"53","author":"Wu","year":"2021","journal-title":"Nat. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1038\/nature10983","article-title":"The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups","volume":"486","author":"Curtis","year":"2012","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1038\/s42003-021-02361-1","article-title":"Multiplexed imaging analysis of the tumor-immune microenvironment reveals predictors of outcome in triple-negative breast cancer","volume":"4","author":"Patwa","year":"2021","journal-title":"Commun. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/s41587-023-01767-y","article-title":"Dictionary learning for integrative, multimodal and scalable single-cell analysis","volume":"42","author":"Hao","year":"2024","journal-title":"Nat. Biotechnol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: An R package for comparing biological themes among gene clusters","volume":"16","author":"Yu","year":"2012","journal-title":"Omics A J. Integr. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/j.cels.2015.12.004","article-title":"The Molecular Signatures Database (MSigDB) hallmark gene set collection","volume":"1","author":"Liberzon","year":"2015","journal-title":"Cell Syst."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.autrev.2009.03.011","article-title":"SERPINB3, apoptosis and autoimmunity","volume":"9","author":"Vidalino","year":"2009","journal-title":"Autoimmun. Rev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.semcdb.2016.09.005","article-title":"SERPINB3 and B4: From biochemistry to biology","volume":"62","author":"Sun","year":"2017","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1016\/S1665-2681(19)30974-3","article-title":"Role of SERPINB3 in hepatocellular carcinoma","volume":"13","author":"Pontisso","year":"2014","journal-title":"Ann. Hepatol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Ye, Y., Yu, S., Guo, T., Zhang, S., Shen, X., and Han, G. (2024). Epithelial-Mesenchymal Transition in Non-Small Cell Lung Cancer Management: Opportunities and Challenges. Biomolecules, 14.","DOI":"10.3390\/biom14121523"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Cagnin, S., Pontisso, P., and Martini, A. (2024). SerpinB3: A Multifaceted Player in Health and Disease\u2014Review and Future Perspectives. Cancers, 16.","DOI":"10.20944\/preprints202406.0851.v1"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1038\/s41586-019-1922-8","article-title":"B cells and tertiary lymphoid structures promote immunotherapy response","volume":"577","author":"Helmink","year":"2020","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1038\/s41586-019-1914-8","article-title":"Tertiary lymphoid structures improve immunotherapy and survival in melanoma","volume":"577","author":"Cabrita","year":"2020","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1101\/gad.314617.118","article-title":"Roles of the immune system in cancer: From tumor initiation to metastatic progression","volume":"32","author":"Gonzalez","year":"2018","journal-title":"Genes Dev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1038\/s41392-025-02241-8","article-title":"Neuro-immune crosstalk in cancer: Mechanisms and therapeutic implications","volume":"10","author":"Pu","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/s41577-019-0218-4","article-title":"Tumour-intrinsic resistance to immune checkpoint blockade","volume":"20","author":"Kalbasi","year":"2020","journal-title":"Nat. Rev. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1038\/s41392-024-01979-x","article-title":"Cold and hot tumors: From molecular mechanisms to targeted therapy","volume":"9","author":"Wu","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/j.immuni.2018.03.004","article-title":"Cancer-Cell-Intrinsic Mechanisms Shaping the Tumor Immune Landscape","volume":"48","author":"Wellenstein","year":"2018","journal-title":"Immunity"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1186\/s13046-025-03527-z","article-title":"Crosstalk between heterogeneous cancer-associated fibroblast subpopulations and the immune system in breast cancer: Key players and promising therapeutic targets","volume":"44","author":"Liu","year":"2025","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1038\/s41467-025-56275-1","article-title":"Micro Immune Response On-chip (MIRO) models the tumour-stroma interface for immunotherapy testing","volume":"16","author":"Perucca","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e176749","DOI":"10.1172\/jci.insight.176749","article-title":"Highly multiplexed imaging reveals prognostic immune and stromal spatial biomarkers in breast cancer","volume":"10","author":"Eng","year":"2025","journal-title":"JCI Insight"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5665","DOI":"10.1038\/s41467-023-40841-6","article-title":"MYC Deregulation and PTEN Loss Model Tumor and Stromal Heterogeneity of Aggressive Triple-Negative Breast Cancer","volume":"14","author":"Doha","year":"2023","journal-title":"Nature Communications"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"400","DOI":"10.3390\/pathophysiology30030031","article-title":"Unraveling MYC\u2019s Role in Orchestrating Tumor Intrinsic and Tumor Microenvironment Interactions Driving Tumorigenesis and Drug Resistance","volume":"30","author":"Doha","year":"2023","journal-title":"Pathophysiology"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/1\/38\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,2]],"date-time":"2026-01-02T05:13:29Z","timestamp":1767330809000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/1\/38"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,31]]},"references-count":31,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["genes17010038"],"URL":"https:\/\/doi.org\/10.3390\/genes17010038","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,31]]}}}