GLP-1 Targeting Agents Impair Chemoimmunotherapy Effectiveness in Triple-Negative Breast Cancer

GLP-1 Targeting Agents Impair Chemoimmunotherapy Effectiveness 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 Article GLP-1 Targeting Agents Impair Chemoimmunotherapy Effectiveness in Triple-Negative Breast Cancer Joshua Gruber, Bethania Soares dos Santos, Maycon Marção, Ishrat Durdana, and 13 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8380296/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 Activation of glucagon-like peptide-1 receptor (GLP-1R) could affect cancer treatment responses through direct action in tumor or immune cells. However, the field lacks a comprehensive assessment of GLP-1R expression and activity across human tumors. Herein, we report detection GLP-1R across multiple human tumor types and focus on triple-negative breast cancer (TNBC) for deeper analysis. In TNBC, GLP-1R is present in immune and tumor cell compartments. GLP-1 treatment of cancer cells activated survival pathways, drove proliferation, induced paclitaxel resistance and dampened cytokine secretion, effects that required expression of GLP-1R. Spatial transcriptomics of human tumors revealed that GLP-1 exposure remodeled the tumor microenvironment, promoted a mesenchymal transition in malignant cells and disrupted productive macrophage inflammation in tumor-proximate niches. Patients taking GLP-1 drugs during neoadjuvant chemotherapy experienced reduced pathological complete response rates (pCR: 30.8%) compared to controls (65%, p<0.001). Thus, GLP-1-exposure acts on tumor and immune cells to impair chemoimmunotherapy efficacy in TNBC. Biological sciences/Cancer/Cancer microenvironment Biological sciences/Cancer/Gynaecological cancer Full Text Additional Declarations Consent was waived by the respective IRBs (UT Southwestern, City of Hope) for the retrospective patient analyses; consent to publish was waived. Clinical samples were obtained under UT Southwestern IRB approval that included informed consent for sample collection and publication of results. There is NO Competing Interest. Supplementary Files Table1.xlsx Table 1 Suppl.Fig.S3.png Supplementary Figure S3: Proportion of GLP-1R+ cells across cell types in TNBC specimens stratified by GLP-1RA exposure Suppl.Fig.S2.png Supplementary Figure S2: Cytokines unaffected by GLP-1 stimulation Suppl.Fig.S1.png Supplementary Figure S1: Semaglutide dose–response of GLP-1R+ HCC1187 cells measured by CellTiter-Glo Table2.xlsx Table 2 SupplementaryTableS2.xlsx Supplementary Table 2 SupplementaryTableS1.xlsx Supplementary Table 1 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. 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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-8380296","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":568557641,"identity":"078feee2-8c9d-4b41-9484-eeb94da47805","order_by":0,"name":"Joshua 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