Paradoxical Roles of Immune-Related Genes in Prostate Cancer Lymph Node Metastasis: A Mendelian Randomisation Study of Single-Cell Expression Quantitative Trait Loci

Paradoxical Roles of Immune-Related Genes in Prostate Cancer Lymph Node Metastasis: A Mendelian Randomisation Study of Single-Cell Expression Quantitative Trait Loci | 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 Paradoxical Roles of Immune-Related Genes in Prostate Cancer Lymph Node Metastasis: A Mendelian Randomisation Study of Single-Cell Expression Quantitative Trait Loci Shuang Li, Yizhao Liu, Ruisong Wang, Qin Zhou This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7285798/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract Lymph node metastasis marks a critical transition in prostate cancer progression, yet causal molecular links between primary tumour immunity and metastatic capability remain unclear. We analysed 425 primary prostate cancer patients, integrating transcriptomic profiling with Mendelian randomisation to establish causal relationships between immune cell gene expression and lymph node metastasis. Differential expression analysis identified 131 significantly altered genes between N1 and N0 tumours. Functional enrichment revealed upregulated genes enriched in metal ion homeostasis, whilst downregulated genes involved viral defence and interferon signalling. Mendelian randomisation identified 11 significant causal associations, with 64% demonstrating protective effects. MT1F showed consistent protection across immune cell types, whilst CD38, GNMT, and SLC14A1 paradoxically increased risk despite upregulation in metastatic tumours. A 7-gene prognostic signature independently predicted progression-free survival across validation cohorts. This study reveals the paradoxical nature of immune-related genes: promoting metastasis when expressed in cancer cells whilst providing protection when expressed in immune cells. Systematic immune suppression creates corrupted microenvironments where protective genes are co-opted for cancer survival. Effective immunotherapy strategies must account for this dual nature, necessitating multi-dimensional precision medicine approaches that target specific cellular compartments. Prostate Cancer sceQTL Immune cells Metastasis Full Text Additional Declarations No competing interests reported. Supplementary Files supplementaryTableS1.csv supplementaryTableS2.csv Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 27 Oct, 2025 Reviews received at journal 19 Oct, 2025 Reviews received at journal 16 Oct, 2025 Reviewers agreed at journal 14 Oct, 2025 Reviewers agreed at journal 13 Oct, 2025 Reviewers invited by journal 04 Sep, 2025 Editor invited by journal 02 Sep, 2025 Editor assigned by journal 01 Sep, 2025 Submission checks completed at journal 11 Aug, 2025 First submitted to journal 11 Aug, 2025 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-7285798","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":512477277,"identity":"383abcb7-1d06-4925-8dc8-cb094f68482d","order_by":0,"name":"Shuang Li","email":"","orcid":"","institution":"The First People's Hospital of Changde City","correspondingAuthor":false,"prefix":"","firstName":"Shuang","middleName":"","lastName":"Li","suffix":""},{"id":512477279,"identity":"a6e3c58c-e252-4dca-a8ca-a814ff3d07c1","order_by":1,"name":"Yizhao Liu","email":"","orcid":"","institution":"The First People's Hospital of Changde 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