Targeting MDA5 enhances tumor immunity through immunogenic cell death and augments the efficacy of immune checkpoint blockade

Targeting MDA5 enhances tumor immunity through immunogenic cell death and augments the efficacy of immune checkpoint blockade | 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 Targeting MDA5 enhances tumor immunity through immunogenic cell death and augments the efficacy of immune checkpoint blockade wenyu wang, zhitong Niu, Bing Cheng, yue Jiang, Yingzhen Weng, and 14 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8094898/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 Identifying targets to enhance tumor immunity is an urgent need. Although nucleic acid sensors play critical roles in promoting tumor immune clearance, their exceptionally low mutation rate in cancers suggests potential unexplored roles in tumor progression. Here, we demonstrated that the RNA sensor MDA5 promotes immune evasion, and its high expression was strongly predictive of poor survival and resistance to immune checkpoint blockade (ICB) therapy in patients. Targeting MDA5 reshapes the tumor microenvironment, strengthening immune memory responses and enhancing effector CD8⁺ T cell activity. Mechanistically, MDA5 deficiency triggers UPR-driven immunogenic cell death (ICD) through induction of damage-associated molecular patterns (DAMPs), leading to enhanced dendritic cell-mediated antigen engulfment and T cell activation. Additionally, MDA5 loss primes the ASK1-JNK/P38 signaling pathway, sensitizing tumor cells to TNFα/IFNγ, further amplifying this process. Consequently, targeting MDA5 enhances the efficacy of ICB therapy across multiple cancer types, positioning it as a promising therapeutic target. Biological sciences/Cancer/Cancer therapy/Targeted therapies Health sciences/Diseases/Cancer/Tumour immunology/Immunosurveillance Full Text Additional Declarations Yes there is potential Competing Interest. W.W., B.C., Z.N., X.W. and Y.C. are inventors of patent applications related to the technology described in this paper. The other authors declare no competing interests. Supplementary Files Supplementaryfiles.pdf supplementary figures1-10 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-8094898","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":557025615,"identity":"56e4eaea-abb5-47f0-b21c-92d9dc1e4eeb","order_by":0,"name":"wenyu 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