Mechanism of ASIC4 in Regulating MHC-I-Mediated Immune Evasion in Pancreatic Cancer

Mechanism of ASIC4 in Regulating MHC-I-Mediated Immune Evasion in Pancreatic 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 Research Article Mechanism of ASIC4 in Regulating MHC-I-Mediated Immune Evasion in Pancreatic Cancer Qi An This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7975326/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 24 Feb, 2026 Read the published version in Journal of Translational Medicine → Version 1 posted 4 You are reading this latest preprint version Abstract Immune evasion is a major cause of the poor efficacy of therapies for pancreatic ductal adenocarcinoma (PDAC). However, the underlying mechanism by which MHC-I downregulation leads to low infiltration of cytotoxic T lymphocytes in PDAC remains incompletely elucidated. This study aims to identify the molecules responsible for the low expression of MHC-I and potential novel therapeutic targets, thereby providing a theoretical foundation for reversing immune evasion in pancreatic cancer. Methods: Bioinformatic analysis identified the acid-sensing ion channel (ASIC4) as a key factor associated with low cytotoxic T lymphocyte (CTL) infiltration in pancreatic ductal adenocarcinoma (PDAC). The correlation between ASIC4 expression and patient prognosis was analyzed via immunohistochemistry (IHC). To elucidate the molecular mechanism by which ASIC4 mediates immune evasion in PDAC, we comprehensively utilized Western blotting, co-immunoprecipitation, and immunofluorescence. An orthotopic PDAC mouse model was established to assess the impact of ASIC4 deletion on CD8⁺ T cell infiltration and tumor growth in vivo. Results: The study found that in pancreatic ductal adenocarcinoma (PDAC), the expression of ASIC4 was significantly upregulated and negatively correlated with the low expression of Major Histocompatibility Complex class I (MHC-I), which was associated with poor patient prognosis. Notably, knocking down ASIC4 led to a significant increase in CD8 + T cell infiltration and slowed tumor growth in vivo. Mechanistic investigations revealed that ASIC4 knockdown restored total and surface levels of MHC-I by inhibiting its autophagic-lysosomal degradation. Conclusion: This study revealed that ASIC4 is highly expressed in PDAC, and its elevated expression is significantly associated with poor prognosis in pancreatic cancer patients. Further mechanistic investigations demonstrated that ASIC4 promotes the degradation of MHC-I via the lysosomal pathway. The subsequent reduction in MHC-I expression leads to decreased infiltration of cytotoxic T lymphocytes (CTLs), ultimately accelerating pancreatic cancer progression. Silencing ASIC1 restored MHC-I expression and enhanced the antitumor efficacy of CD8⁺ T cells. These findings identify ASIC4 as a potential therapeutic target and provide a theoretical foundation for reversing the immune-cold phenotype of PDAC and developing combined immunotherapy strategies. Full Text Cite Share Download PDF Status: Published Journal Publication published 24 Feb, 2026 Read the published version in Journal of Translational Medicine → Version 1 posted Reviewers agreed at journal 04 Nov, 2025 Reviewers invited by journal 03 Nov, 2025 Editor assigned by journal 31 Oct, 2025 First submitted to journal 28 Oct, 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. 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-7975326","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":539529769,"identity":"689ac940-beac-4f00-9b43-424806934f7a","order_by":0,"name":"Qi 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Cancer","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-translational-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jtrm","sideBox":"Learn more about [Journal of Translational Medicine](http://translational-medicine.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/jtrm/default.aspx","title":"Journal of Translational Medicine","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7975326/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7975326/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eImmune evasion is a major cause of the poor efficacy of therapies for pancreatic ductal adenocarcinoma (PDAC). However, the underlying mechanism by which MHC-I downregulation leads to low infiltration of cytotoxic T lymphocytes in PDAC remains incompletely elucidated. This study aims to identify the molecules responsible for the low expression of MHC-I and potential novel therapeutic targets, thereby providing a theoretical foundation for reversing immune evasion in pancreatic cancer.\u003c/p\u003e\u003cp\u003eMethods:\u003c/p\u003e\u003cp\u003eBioinformatic analysis identified the acid-sensing ion channel (ASIC4) as a key factor associated with low cytotoxic T lymphocyte (CTL) infiltration in pancreatic ductal adenocarcinoma (PDAC). The correlation between ASIC4 expression and patient prognosis was analyzed via immunohistochemistry (IHC). To elucidate the molecular mechanism by which ASIC4 mediates immune evasion in PDAC, we comprehensively utilized Western blotting, co-immunoprecipitation, and immunofluorescence. An orthotopic PDAC mouse model was established to assess the impact of ASIC4 deletion on CD8⁺ T cell infiltration and tumor growth in vivo.\u003c/p\u003e\u003cp\u003eResults:\u003c/p\u003e\u003cp\u003eThe study found that in pancreatic ductal adenocarcinoma (PDAC), the expression of ASIC4 was significantly upregulated and negatively correlated with the low expression of Major Histocompatibility Complex class I (MHC-I), which was associated with poor patient prognosis. Notably, knocking down ASIC4 led to a significant increase in CD8\u0026thinsp;+\u0026thinsp;T cell infiltration and slowed tumor growth in vivo. Mechanistic investigations revealed that ASIC4 knockdown restored total and surface levels of MHC-I by inhibiting its autophagic-lysosomal degradation.\u003c/p\u003e\u003cp\u003eConclusion:\u003c/p\u003e\u003cp\u003eThis study revealed that ASIC4 is highly expressed in PDAC, and its elevated expression is significantly associated with poor prognosis in pancreatic cancer patients. Further mechanistic investigations demonstrated that ASIC4 promotes the degradation of MHC-I via the lysosomal pathway. The subsequent reduction in MHC-I expression leads to decreased infiltration of cytotoxic T lymphocytes (CTLs), ultimately accelerating pancreatic cancer progression. Silencing ASIC1 restored MHC-I expression and enhanced the antitumor efficacy of CD8⁺ T cells. These findings identify ASIC4 as a potential therapeutic target and provide a theoretical foundation for reversing the immune-cold phenotype of PDAC and developing combined immunotherapy strategies.\u003c/p\u003e","manuscriptTitle":"Mechanism of ASIC4 in Regulating MHC-I-Mediated Immune Evasion in Pancreatic Cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-13 19:17:32","doi":"10.21203/rs.3.rs-7975326/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2025-11-04T12:19:13+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-11-04T03:59:49+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-31T15:37:13+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Translational Medicine","date":"2025-10-29T00:08:02+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-translational-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jtrm","sideBox":"Learn more about [Journal of Translational Medicine](http://translational-medicine.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/jtrm/default.aspx","title":"Journal of Translational Medicine","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"41236a5b-2bb0-414e-b2d5-642fa48e8bcb","owner":[],"postedDate":"November 13th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-03-02T16:01:43+00:00","versionOfRecord":{"articleIdentity":"rs-7975326","link":"https://doi.org/10.1186/s12967-026-07880-1","journal":{"identity":"journal-of-translational-medicine","isVorOnly":false,"title":"Journal of Translational Medicine"},"publishedOn":"2026-02-24 15:58:32","publishedOnDateReadable":"February 24th, 2026"},"versionCreatedAt":"2025-11-13 19:17:32","video":"","vorDoi":"10.1186/s12967-026-07880-1","vorDoiUrl":"https://doi.org/10.1186/s12967-026-07880-1","workflowStages":[]},"version":"v1","identity":"rs-7975326","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7975326","identity":"rs-7975326","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}