Endocytic mechano-metabolic feedback linking tissue fluidity to mitochondrial DNA–dependent immunity in breast cancer

Endocytic mechano-metabolic feedback linking tissue fluidity to mitochondrial DNA–dependent immunity in 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 Endocytic mechano-metabolic feedback linking tissue fluidity to mitochondrial DNA–dependent immunity in breast cancer Giorgio Scita, Andrea Palamidessi, Emanuela Frittoli, Monica Corada, and 24 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5281971/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Why some tumors are "hot" and respond to immunotherapy while others remain "cold" is a central challenge in oncology. Here, we identify a mechanical process that, while driving malignant invasion, paradoxically converts immunologically "cold" tumors "hot." Previous evidence indicates that the transition from in situ to invasive breast carcinoma is driven by tissue fluidization mediated by pathologically elevated RAB5A-dependent endocytosis. This fluidization generates mechanical stress leading to a robust cGASdependent transcriptional rewiring. Here, we investigated its mechanistic and immunological consequences. We find that the pathological RAB5A elevation defines an immune-active transcriptional program that predicts improved survival in triple-negative and HER2-positive breast cancers. We further show that RAB5A-driven fluidization elicits a mechano-metabolic response characterized by profound mitochondrial elongation through dysregulation of the AMPK–AKAP1–DRP1 fission pathway. Mechanical and metabolic stress, together with RAB5A-vesicle interactions on hyperfused mitochondria, compromise mitochondrial integrity by triggering a RAB5ABAX/BAK-mediated pore formation. This event enhances GASDERMIN A expression, which becomes palmitoylated and oligomerizes on mitochondria, establishing a positive feedback loop that amplifies minority mitochondrial outer-membrane permeabilization (miMOMP). This sub-lethal miMOMP causes mitochondrial damage and the release of mitochondrial DNA (mtDNA), which potently activates the cGAS/STING innate immune axis, explaining the observed hyper inflammatory state.Consequently, RAB5A-expressing tumors in immunocompetent mice exhibit slow growth, enhanced immune infiltration, and heightened sensitivity to immune-checkpoint blockade in a BAX/BAK-, cGAS/STING- and mtDNA-dependent fashion. These findings reveal a novel interplay between mechanical stress, mitochondrial dynamics and integrity, and immune activation, presenting new therapeutic opportunities to boost antitumor immunity in cancer therapy. Biological sciences/Cancer/Breast cancer Biological sciences/Cell biology/Cell migration/Collective cell migration Full Text Additional Declarations There is NO Competing Interest. Supplementary Files MovieS3.mp4 Movie S3 MovieS7.mp4 Movie S7 MovieS5.mp4 Movie S5 MovieS2.mp4 Movie S2 MovieS6.mp4 Movie S6 MovieS4.mp4 Movie S4 MovieS1.mp4 Movie S1 Cite Share Download PDF Status: Under Review 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-5281971","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":561390260,"identity":"8cfccc93-87a7-448b-80da-56f35246fbeb","order_by":0,"name":"Giorgio 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Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-5281971/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5281971/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Why some tumors are \"hot\" and respond to immunotherapy while others remain \"cold\" is a central challenge in oncology. Here, we identify a mechanical process that, while driving malignant invasion, paradoxically converts immunologically \"cold\" tumors \"hot.\" Previous evidence indicates that the transition from in situ to invasive breast carcinoma is driven by tissue fluidization mediated by pathologically elevated RAB5A-dependent endocytosis. This fluidization generates mechanical stress leading to a robust cGASdependent transcriptional rewiring. Here, we investigated its mechanistic and immunological consequences. We find that the pathological RAB5A elevation defines an immune-active transcriptional program that predicts improved survival in triple-negative and HER2-positive breast cancers. We further show that RAB5A-driven fluidization elicits a mechano-metabolic response characterized by profound mitochondrial elongation through dysregulation of the\r\nAMPK–AKAP1–DRP1 fission pathway. Mechanical and metabolic stress, together with RAB5A-vesicle interactions on hyperfused mitochondria, compromise mitochondrial integrity by triggering a RAB5ABAX/BAK-mediated pore formation. This event enhances GASDERMIN A expression, which becomes palmitoylated and oligomerizes on mitochondria, establishing a positive feedback loop that amplifies minority mitochondrial outer-membrane permeabilization (miMOMP). This sub-lethal miMOMP causes mitochondrial damage and the release of mitochondrial DNA (mtDNA), which potently activates the cGAS/STING innate immune axis, explaining the observed hyper inflammatory state.Consequently, RAB5A-expressing tumors in immunocompetent mice exhibit slow growth, enhanced immune infiltration, and heightened sensitivity to immune-checkpoint blockade in a BAX/BAK-, cGAS/STING- and mtDNA-dependent fashion. These findings reveal a novel interplay between mechanical stress, mitochondrial dynamics and integrity, and immune activation, presenting new therapeutic opportunities to boost antitumor immunity in cancer therapy.","manuscriptTitle":"Endocytic mechano-metabolic feedback linking tissue fluidity to mitochondrial DNA–dependent immunity in breast cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-17 07:51:29","doi":"10.21203/rs.3.rs-5281971/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"9da79864-20bd-4425-abb1-09d0d695976d","owner":[],"postedDate":"December 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":59776426,"name":"Biological sciences/Cancer/Breast cancer"},{"id":59776427,"name":"Biological sciences/Cell biology/Cell migration/Collective cell migration"}],"tags":[],"updatedAt":"2026-03-30T17:27:21+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-17 07:51:29","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5281971","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5281971","identity":"rs-5281971","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}