{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T23:01:50Z","timestamp":1784847710737,"version":"3.55.0"},"posted":{"date-parts":[[2026,7,21]]},"group-title":"Immunology","reference-count":50,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T00:00:00Z","timestamp":1784592000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"American Lung Association Innovation Award","award":["IA-1613730 to H. L."],"award-info":[{"award-number":["IA-1613730 to H. L."]}]},{"name":"The Ohio State University Comprehensive Cancer Center Startup Fund","award":["To H. L."],"award-info":[{"award-number":["To H. L."]}]},{"name":"The OSU Internal Funds","award":["To H.L."],"award-info":[{"award-number":["To H.L."]}]},{"name":"NIH\/NIAID award","award":["1R01AI183671-01A1 to J. L."],"award-info":[{"award-number":["1R01AI183671-01A1 to J. L."]}]},{"name":"NIH\/NCI award","award":["5U01CA294881 to J. L."],"award-info":[{"award-number":["5U01CA294881 to J. L."]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Lung cancer is the leading cause of cancer-related mortality worldwide, with only approximately 30% of patients benefiting from current immune checkpoint immunotherapy. Oncolytic virotherapy offers a promising strategy to overcome this resistance; however, achieving both potent tumor cytotoxicity and robust antitumor immune activation remains a major challenge. Here, we engineered oncolytic measles virus expressing the tumor suppressor MG53 (TRIM72), designated rMeV-MG53, and evaluated its therapeutic potential against non-small cell lung cancer (NSCLC). rMeV-MG53 retained replication kinetics comparable to parental MeV while driving significantly greater cytotoxicity than an unarmed control in NSCLC cells. Mechanistically, MG53 arming amplified caspase-3\u2013dependent apoptosis and potentiated Gasdermin E (GSDME) cleavage, engaging GSDME-mediated pyroptosis as a key tumor-killing mechanism; pharmacological inhibition confirmed caspase-dependent apoptosis as the initiating event leading to pyroptosis, while excluding necroptosis and ferroptosis as significant contributors to rMeV-MG53-induced cytotoxicity. MG53 overexpression induced an intrinsic pro-inflammatory transcriptional signature enriched for TNF, NF-\u03baB, and IL-17 signaling, and rMeV-MG53 elicited significantly stronger type I interferon and pro-inflammatory cytokine induction than the unarmed control. In an immunocompetent, MeV-permissive syngeneic NSCLC model, intratumoral rMeV-MG53 achieved superior tumor growth inhibition, amplified caspase-3\/GSDME pyroptosis, selectively upregulated\n                  <jats:italic>Cxcl10<\/jats:italic>\n                  ,\n                  <jats:italic>Ifng<\/jats:italic>\n                  , and\n                  <jats:italic>Il1b<\/jats:italic>\n                  , and drove robust CD8\u207a T-cell and Granzyme B\u207a effector infiltration. This immune remodeling was accompanied by compensatory PD-L1 upregulation, and combining rMeV-MG53 with anti-PD-L1 blockade achieved the strongest tumor suppression of all treatment groups. These findings establish MG53-armed oncolytic MeV as a strategy coupling GSDME-mediated pyroptosis with antitumor immune remodeling to sensitize immune-resistant NSCLC to checkpoint immunotherapy.\n                <\/jats:p>","DOI":"10.64898\/2026.07.15.738733","type":"posted-content","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T18:00:18Z","timestamp":1784656818000},"source":"Crossref","is-referenced-by-count":0,"title":["Engineering Oncolytic Measles Virus with MG53 Couples Pyroptotic Tumor Killing with Immune Microenvironment Remodeling to Enhance Checkpoint Immunotherapy in Non-small Cell Lung Cancer"],"prefix":"10.64898","author":[{"given":"Zhongguang","family":"Li","sequence":"first","affiliation":[{"name":"Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210 USA"},{"name":"The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng Chih","family":"Hsu","sequence":"additional","affiliation":[{"name":"Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Bu","sequence":"additional","affiliation":[{"name":"Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Umme","family":"Lubaba","sequence":"additional","affiliation":[{"name":"Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210 USA"},{"name":"The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sally L.","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serena li","family":"Zhao","sequence":"additional","affiliation":[{"name":"The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210 USA"},{"name":"Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University, Columbus, OH 43210 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei-Hui","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hunter J.","family":"Piegols","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences, The Ohio State University, Columbus, OH 43210 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuefeng","family":"Liu","sequence":"additional","affiliation":[{"name":"The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210 USA"},{"name":"Departments of Pathology, Urology and Radiation Oncology, The Ohio State University, Columbus, OH 43210 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianrong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210 USA"},{"name":"Infectious Disease Institute, The Ohio State University, Columbus, OH 43210 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9784-6480","authenticated-orcid":false,"given":"Haichang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210 USA"},{"name":"The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026072315302067000_2026.07.15.738733v1.1","doi-asserted-by":"publisher","DOI":"10.3322\/CAAC.21834"},{"key":"2026072315302067000_2026.07.15.738733v1.2","doi-asserted-by":"publisher","DOI":"10.1097\/CM9.0000000000002529"},{"key":"2026072315302067000_2026.07.15.738733v1.3","doi-asserted-by":"publisher","DOI":"10.3322\/caac.70043"},{"key":"2026072315302067000_2026.07.15.738733v1.4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1504627"},{"key":"2026072315302067000_2026.07.15.738733v1.5","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1507643"},{"key":"2026072315302067000_2026.07.15.738733v1.6","doi-asserted-by":"crossref","unstructured":"J. Y. Sun et al., Resistance to PD-1\/PD-L1 blockade cancer immunotherapy: mechanisms, predictive factors, and future perspectives. Biomark Res 8, 35 (2020).","DOI":"10.1186\/s40364-020-00212-5"},{"key":"2026072315302067000_2026.07.15.738733v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.06.001"},{"key":"2026072315302067000_2026.07.15.738733v1.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2016.11.007"},{"key":"2026072315302067000_2026.07.15.738733v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1812"},{"key":"2026072315302067000_2026.07.15.738733v1.10","first-page":"139r","article-title":"Recombinant MG53 protein modulates therapeutic cell membrane repair in treatment of muscular dystrophy","volume":"4","year":"2012","journal-title":"Sci Transl Med"},{"key":"2026072315302067000_2026.07.15.738733v1.11","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms5387"},{"key":"2026072315302067000_2026.07.15.738733v1.12","doi-asserted-by":"crossref","first-page":"1886","DOI":"10.1111\/jcmm.16917","article-title":"MG53 attenuates nitrogen mustard-induced acute lung injury","volume":"26","year":"2022","journal-title":"J Cell Mol Med"},{"key":"2026072315302067000_2026.07.15.738733v1.13","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2014.12.010"},{"key":"2026072315302067000_2026.07.15.738733v1.14","first-page":"279r","article-title":"MG53-mediated cell membrane repair protects against acute kidney injury","volume":"7","year":"2015","journal-title":"Sci Transl Med"},{"key":"2026072315302067000_2026.07.15.738733v1.15","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.kint.2021.09.027","article-title":"The cell membrane repair protein MG53 modulates transcription factor NF-kappaB signaling to control kidney fibrosis","volume":"101","year":"2022","journal-title":"Kidney Int"},{"key":"2026072315302067000_2026.07.15.738733v1.16","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.680074"},{"key":"2026072315302067000_2026.07.15.738733v1.17","doi-asserted-by":"crossref","unstructured":"H. Li et al., MG53 Mitigates Nitrogen Mustard-Induced Skin Injury. Cells 12 (2023).","DOI":"10.3390\/cells12141915"},{"key":"2026072315302067000_2026.07.15.738733v1.18","doi-asserted-by":"crossref","unstructured":"Z. Li et al., MG53 protects against intestinal inflammation by inhibiting NLRP3 inflammasome activation. Front Pharmacol 17, 1791509 (2026).","DOI":"10.3389\/fphar.2026.1791509"},{"key":"2026072315302067000_2026.07.15.738733v1.19","doi-asserted-by":"crossref","unstructured":"Z. Li et al., MG53, A Tissue Repair Protein with Broad Applications in Regenerative Medicine. Cells 10 (2021).","DOI":"10.3390\/cells10010122"},{"key":"2026072315302067000_2026.07.15.738733v1.20","doi-asserted-by":"crossref","unstructured":"H. Li et al., MG53 suppresses tumor progression and stress granule formation by modulating G3BP2 activity in non-small cell lung cancer. Mol Cancer 20, 118 (2021).","DOI":"10.1186\/s12943-021-01418-3"},{"key":"2026072315302067000_2026.07.15.738733v1.21","doi-asserted-by":"crossref","first-page":"5221","DOI":"10.7150\/ijbs.67869","article-title":"MG53 inhibits cellular proliferation and tumor progression in colorectal carcinoma","volume":"18","year":"2022","journal-title":"Int J Biol Sci"},{"key":"2026072315302067000_2026.07.15.738733v1.22","doi-asserted-by":"crossref","unstructured":"M. Fang et al., E3 ligase MG53 suppresses tumor growth by degrading cyclin D1. Signal Transduct Target Ther 8, 263 (2023).","DOI":"10.1038\/s41392-023-01458-9"},{"key":"2026072315302067000_2026.07.15.738733v1.23","doi-asserted-by":"crossref","unstructured":"X. L. Wang et al., MG53 suppresses tumor growth via transcriptional inhibition of KIF11 in pancreatic cancer. Transl Oncol 50, 102118 (2024).","DOI":"10.1016\/j.tranon.2024.102118"},{"key":"2026072315302067000_2026.07.15.738733v1.24","doi-asserted-by":"crossref","first-page":"e1805492","DOI":"10.1002\/smll.201805492","article-title":"MG53 Inhibits the Progression of Tongue Cancer Cells through Regulating PI3K-AKT Signaling Pathway: Evidence from 3D Cell Culture and Animal Model","volume":"15","year":"2019","journal-title":"Small"},{"key":"2026072315302067000_2026.07.15.738733v1.25","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.cytogfr.2020.07.009","article-title":"Mechanisms of measles virus oncolytic immunotherapy","volume":"56","year":"2020","journal-title":"Cytokine Growth Factor Rev"},{"key":"2026072315302067000_2026.07.15.738733v1.26","doi-asserted-by":"crossref","unstructured":"S. R. Volovat et al., Oncolytic Virotherapy: A New Paradigm in Cancer Immunotherapy. Int J Mol Sci 25 (2024).","DOI":"10.3390\/ijms25021180"},{"key":"2026072315302067000_2026.07.15.738733v1.27","first-page":"774","article-title":"Oncolytic Measles Virus Encoding Interleukin-12 Mediated Antitumor Activity and Immunologic Control of Colon Cancer In Vivo and Ex Vivo","volume":"36","year":"2021","journal-title":"Cancer Biother Radiopharm"},{"key":"2026072315302067000_2026.07.15.738733v1.28","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2016.67.1529"},{"key":"2026072315302067000_2026.07.15.738733v1.29","first-page":"43","article-title":"Clinical testing of engineered oncolytic measles virus strains in the treatment of cancer: an overview","volume":"11","year":"2009","journal-title":"Curr Opin Mol Ther"},{"key":"2026072315302067000_2026.07.15.738733v1.30","doi-asserted-by":"crossref","unstructured":"C. E. Engeland , G. Ungerechts , Measles Virus as an Oncolytic Immunotherapy. Cancers (Basel ) 13 (2021).","DOI":"10.3390\/cancers13030544"},{"key":"2026072315302067000_2026.07.15.738733v1.31","doi-asserted-by":"crossref","unstructured":"A. Wu et al., Recombinant measles virus vaccine rMV-Hu191 exerts an oncolytic effect on esophageal squamous cell carcinoma via caspase-3\/GSDME-mediated pyroptosis. Cell Death Discov 9, 171 (2023).","DOI":"10.1038\/s41420-023-01466-2"},{"key":"2026072315302067000_2026.07.15.738733v1.32","doi-asserted-by":"publisher","DOI":"10.1038\/nature22393"},{"key":"2026072315302067000_2026.07.15.738733v1.33","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2071-9"},{"key":"2026072315302067000_2026.07.15.738733v1.34","doi-asserted-by":"crossref","unstructured":"M. Lu et al., A safe and highly efficacious measles virus-based vaccine expressing SARS-CoV-2 stabilized prefusion spike. Proc Natl Acad Sci U S A 118 (2021).","DOI":"10.1073\/pnas.2026153118"},{"key":"2026072315302067000_2026.07.15.738733v1.35","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2220403120"},{"key":"2026072315302067000_2026.07.15.738733v1.36","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2201616119"},{"key":"2026072315302067000_2026.07.15.738733v1.37","doi-asserted-by":"crossref","first-page":"e28687","DOI":"10.1002\/jmv.28687","article-title":"Recombinant measles virus expressing prefusion spike protein stabilized by six rather than two prolines is more efficacious against SARS-CoV-2 infection","volume":"95","year":"2023","journal-title":"J Med Virol"},{"key":"2026072315302067000_2026.07.15.738733v1.38","first-page":"e2506821122","article-title":"Intranasal measles virus- and mumps virus-based SARS-CoV-2 vaccine candidates prevent SARS-CoV-2 infection and transmission","volume":"122","year":"2025","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2026072315302067000_2026.07.15.738733v1.39","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-49443-2"},{"key":"2026072315302067000_2026.07.15.738733v1.40","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-018-0019-2"},{"key":"2026072315302067000_2026.07.15.738733v1.41","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-04-0884"},{"key":"2026072315302067000_2026.07.15.738733v1.42","doi-asserted-by":"crossref","unstructured":"C. M. Bourne , C. Y. Taabazuing , Harnessing Pyroptosis for Cancer Immunotherapy. Cells 13 (2024).","DOI":"10.3390\/cells13040346"},{"key":"2026072315302067000_2026.07.15.738733v1.43","first-page":"1868","article-title":"Vesicular stomatitis virus sensitizes immunologically cold tumors to checkpoint blockade by inducing pyroptosis","volume":"166538","year":"2022","journal-title":"Biochim Biophys Acta Mol Basis Dis"},{"key":"2026072315302067000_2026.07.15.738733v1.44","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2017.11.007"},{"key":"2026072315302067000_2026.07.15.738733v1.45","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-15-0563"},{"key":"2026072315302067000_2026.07.15.738733v1.46","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaa1348"},{"key":"2026072315302067000_2026.07.15.738733v1.47","doi-asserted-by":"crossref","unstructured":"X. Ma et al., The E3 ubiquitin ligase MG53 inhibits hepatocellular carcinoma by targeting RAC1 signaling. Oncogenesis 11, 40 (2022).","DOI":"10.1038\/s41389-022-00414-6"},{"key":"2026072315302067000_2026.07.15.738733v1.48","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.72.9.7420-7427.1998"},{"key":"2026072315302067000_2026.07.15.738733v1.49","doi-asserted-by":"crossref","first-page":"e0142007","DOI":"10.1371\/journal.pone.0142007","article-title":"Human Genetic Relevance and Potent Antitumor Activity of Heat Shock Protein 90 Inhibition in Canine Lung Adenocarcinoma Cell Lines","volume":"10","year":"2015","journal-title":"PLoS One"},{"key":"2026072315302067000_2026.07.15.738733v1.50","doi-asserted-by":"crossref","unstructured":"K. Tamura et al., Anti-tumor activity of a recombinant measles virus against canine lung cancer cells. Sci Rep 13, 18168 (2023).","DOI":"10.1038\/s41598-023-42305-9"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.07.15.738733","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T22:30:37Z","timestamp":1784845837000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.07.15.738733"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,21]]},"references-count":50,"URL":"https:\/\/doi.org\/10.64898\/2026.07.15.738733","relation":{},"subject":[],"published":{"date-parts":[[2026,7,21]]},"subtype":"preprint"}}