Distinct Endothelial Phenotype Associates with Macrophage-Enriched Microenvironments in Triple-Negative Breast Cancer

Distinct Endothelial Phenotype Associates with Macrophage-Enriched Microenvironments in Triple-Negative Breast Cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Distinct Endothelial Phenotype Associates with Macrophage-Enriched Microenvironments in Triple-Negative Breast Cancer Luis Becerra-Dominguez, Liqun Yu, Charlotte Helena Rivas, Sergio Aguirre, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8595402/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Triple-negative breast cancer (TNBC) is an aggressive malignancy with limited therapeutic options due to the absence of targetable receptors and pronounced intra-tumoral heterogeneity. Among the various contributors to this heterogeneity, the aberrant tumor vasculature plays a critical role by restricting drug delivery and immune cell infiltration, thereby promoting therapeutic resistance. Using previously established murine TNBC models differing in macrophage abundance, we found marked differences in tumor vasculature between these models. Macrophage-enriched tumors exhibited hallmarks of vascular normalization, including increased pericyte coverage and enhanced lectin-based vessel perfusion compared to macrophage-poor tumors. Single-cell RNA sequencing revealed that endothelial cells from macrophage-enriched tumors upregulated inflammatory and macrophage–monocyte interaction genes, including interferon-γ–responsive pathways, and were enriched for venous-like states. In contrast, non-macrophage-enriched tumors displayed arterial-, lymphatic-, and homeostatic endothelial programs. Analysis of human TNBC single-cell datasets confirmed that endothelial composition and activation state vary with macrophage abundance, with macrophage-enriched tumors exhibiting more immunologically active endothelium. Collectively, these results identify conserved associations between macrophage-enriched microenvironments and vascular states, highlighting coordinated immune–vascular dynamics in TNBC tumors. Triple-Negative Breast Cancer Macrophages Vascular Normalization Endothelial Cells Tumor Microenvironment Full Text Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8595402","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":578384810,"identity":"77f6b25e-7c5f-4d76-a4d7-a25a70d6aa1c","order_by":0,"name":"Luis Becerra-Dominguez","email":"","orcid":"","institution":"Baylor College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Luis","middleName":"","lastName":"Becerra-Dominguez","suffix":""},{"id":578384811,"identity":"c2477b67-7c3f-4d73-8fa2-e0ead9e6b216","order_by":1,"name":"Liqun Yu","email":"","orcid":"","institution":"Baylor College of 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