TNFR2 Promotes Glycolysis to Induce PD-1 Expression Imbalance Between Effector T Cells and Tregs and Confers Immunotherapy Resistance in Cervical Cancer

TNFR2 Promotes Glycolysis to Induce PD-1 Expression Imbalance Between Effector T Cells and Tregs and Confers Immunotherapy Resistance in Cervical 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 TNFR2 Promotes Glycolysis to Induce PD-1 Expression Imbalance Between Effector T Cells and Tregs and Confers Immunotherapy Resistance in Cervical Cancer BaoXia Cui, Qingqing Liu, Jinwen Ye, Yiping Hao, Chuanying Zhao, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8795648/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 Previous studies identified the PD-1 expression ratio between CD8 + effector T cells and Treg in the TME as a predictive marker for immune checkpoint blockade efficacy. Here, we confirmed that PD-1 expression on eTreg is significantly higher than on CD8 + T cells in cervical cancer, explaining the limited response to anti-PD-1 therapy. High TNFR2 expression impairs anti-PD-1 efficacy and exacerbates this PD-1 imbalance. RNA sequencing and untargeted metabolomics showed TNFR2 regulates the Warburg effect: TNFR2 downregulation reduces glucose uptake, lactate secretion, and ATP production, while glycolysis inhibition reverses TNFR2-mediated tumorigenesis in nude mouse xenografts. Lactate was identified as a key mediator of the PD-1 imbalance. Mechanistically, TNFR2 regulates tumor glycolysis via the PI3K/Akt/mTOR/c-Myc pathway, with c-Myc driving glycolytic gene expression. Inhibiting PI3K, mTOR, or c-Myc reverses TNFR2-induced glycolytic enzyme upregulation, while Akt activation restores their expression after TNFR2 downregulation. Our study identifies a novel TNFR2-PI3K/Akt/mTOR/c-Myc-glycolysis-lactate-PD-1 imbalance axis, proposing TNFR2 inhibitors enhance anti-PD-1 efficacy by reversing this imbalance. Combining TNFR2 blockade with anti-PD-1 therapy may improve cervical cancer treatment outcomes. Biological sciences/Cancer/Gynaecological cancer/Cervical cancer Biological sciences/Cancer/Cancer therapy/Cancer therapeutic resistance TNFR2 Glycolysis PD-1 expression imbalance Immunotherapy resistance Treg Full Text Additional Declarations (Not answered) Supplementary Files SupplementaryFigure.docx TNFR2 Promotes Glycolysis to Induce PD-1 Expression Imbalance Between Effector T Cells and Tregs and Confers Immunotherapy Resistance in Cervical Cancer originaldata.pdf original data SupplementaryMaterials.docx Supplementary Figures 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. 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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-8795648","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":593760136,"identity":"7e7f8085-60cd-4adc-9b68-9fb61daa8530","order_by":0,"name":"BaoXia 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