{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T14:57:00Z","timestamp":1791385020412,"version":"4.3.3"},"reference-count":52,"publisher":"American Society for Clinical Investigation","issue":"6","license":[{"start":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T00:00:00Z","timestamp":1773619200000},"content-version":"vor","delay-in-days":83,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Tisch cancer Institute","award":["P30 CA196521"],"award-info":[{"award-number":["P30 CA196521"]}]},{"name":"NIH\/NINDS","award":["R01 NS100864,R21 NS1256000"],"award-info":[{"award-number":["R01 NS100864,R21 NS1256000"]}]},{"name":"NIH\/NCI","award":["1-K08 CA258796-01"],"award-info":[{"award-number":["1-K08 CA258796-01"]}]},{"name":"NIH","award":["R01CA248536"],"award-info":[{"award-number":["R01CA248536"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,3,16]]},"abstract":"<jats:p>\n                    Mutations in DNA mismatch repair (MMR) pathway genes (\n                    <jats:italic>MSH2<\/jats:italic>\n                    ,\n                    <jats:italic>MSH6<\/jats:italic>\n                    ,\n                    <jats:italic>MLH1<\/jats:italic>\n                    , and\n                    <jats:italic>PMS2<\/jats:italic>\n                    ) are linked to acquired resistance to temozolomide (TMZ) and high tumor mutation burden (TMB) in high-grade gliomas (HGGs), including glioblastomas (GBMs). However, the specific roles of individual MMR genes in the initiation, progression, TMB, microsatellite instability (MSI), and resistance to TMZ in gliomas remain unclear. Here, we developed de novo mouse models of germline and somatic MMR-deficient (MMRd) HGGs. Surprisingly, loss of\n                    <jats:italic>Msh2<\/jats:italic>\n                    or\n                    <jats:italic>Msh6<\/jats:italic>\n                    did not lead to high TMB, MSI, nor did it confer a response to anti\u2013programmed cell death 1 (anti\u2013PD-1) in GBM. Similarly, human GBM showed discordance between MMR gene mutations and the TMB and MSI. Germline MMRd promoted the progression from low-grade to HGG and reduced survival compared with MMR-proficient (MMRp) tumor\u2013bearing mice. This effect was not tumor cell intrinsic but was associated with MMRd in the tumor immune microenvironment, driving immunosuppressive myeloid programs, reduced lymphoid infiltration, and CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell exhaustion. Both MMR-reduced (MMRr) and MMRd GBM were resistant to TMZ, unlike MMRp tumors. Our study shows that\n                    <jats:italic>\n                      N\n                      <jats:sup>3<\/jats:sup>\n                    <\/jats:italic>\n                    -(2-fluoroethyl) imidazotetrazine (KL-50), an imidazotetrazine-based DNA targeting agent that induces MMR-independent cross-link\u2013mediated cytotoxicity, was effective against germline and somatic MMRr and MMRd GBMs, offering a potential therapy for TMZ-resistant HGG with MMR alterations.\n                  <\/jats:p>","DOI":"10.1172\/jci195189","type":"journal-article","created":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T17:00:40Z","timestamp":1766509240000},"source":"Crossref","is-referenced-by-count":8,"title":["Mismatch repair deficiency drives malignant progression and alters the tumor immune microenvironment in glioblastoma models"],"prefix":"10.1172","volume":"136","author":[{"given":"Montserrat","family":"Puigdelloses Vallcorba","sequence":"first","affiliation":[{"name":"Departments of Oncological Sciences and Neurosurgery, The Tisch Cancer Institute and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nishant","family":"Soni","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung-Won","family":"Choi","sequence":"additional","affiliation":[{"name":"Departments of Systems Biology and Biomedical Informatics, Columbia University, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kavita","family":"Rawat","sequence":"additional","affiliation":[{"name":"Departments of Oncological Sciences and Neurosurgery, The Tisch Cancer Institute and"},{"name":"Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanvi","family":"Joshi","sequence":"additional","affiliation":[{"name":"Departments of Oncological Sciences and Neurosurgery, The Tisch Cancer Institute and"},{"name":"Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sam","family":"Friedman","sequence":"additional","affiliation":[{"name":"Yale Center for Research Computing, Yale School of Medicine, New Haven, Connecticut, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Buonfiglioli","sequence":"additional","affiliation":[{"name":"Departments of Oncological Sciences and Neurosurgery, The Tisch Cancer Institute and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7713-5833","authenticated-orcid":true,"given":"Angelo","family":"Angione","sequence":"additional","affiliation":[{"name":"Departments of Oncological Sciences and Neurosurgery, The Tisch Cancer Institute and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihong","family":"Chen","sequence":"additional","affiliation":[{"name":"Departments of Oncological Sciences and Neurosurgery, The Tisch Cancer Institute and"},{"name":"Human Immune Monitoring Center and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8510-9598","authenticated-orcid":true,"given":"Gonzalo","family":"Pi\u00f1ero","sequence":"additional","affiliation":[{"name":"Departments of Oncological Sciences and Neurosurgery, The Tisch Cancer Institute and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabrielle","family":"Price","sequence":"additional","affiliation":[{"name":"Departments of Oncological Sciences and Neurosurgery, The Tisch Cancer Institute and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehek","family":"Dedhia","sequence":"additional","affiliation":[{"name":"Departments of Oncological Sciences and Neurosurgery, The Tisch Cancer Institute and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raina","family":"Roche","sequence":"additional","affiliation":[{"name":"Human Immune Monitoring Center and"},{"name":"Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emir","family":"Radkevich","sequence":"additional","affiliation":[{"name":"Human Immune Monitoring Center and"},{"name":"Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne M.","family":"Bowcock","sequence":"additional","affiliation":[{"name":"Departments of Oncological Sciences and Neurosurgery, The Tisch Cancer Institute and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepti","family":"Bhatt","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Winfried","family":"Edelmann","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Albert Einstein College of Medicine, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert M.","family":"Samstein","sequence":"additional","affiliation":[{"name":"Departments of Oncological Sciences and Neurosurgery, The Tisch Cancer Institute and"},{"name":"Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA."},{"name":"Tisch Cancer Institute and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy E.","family":"Richardson","sequence":"additional","affiliation":[{"name":"Tisch Cancer Institute and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadejda M.","family":"Tsankova","sequence":"additional","affiliation":[{"name":"Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7955-4414","authenticated-orcid":true,"given":"Alexander M.","family":"Tsankov","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA."},{"name":"Human Immune Monitoring Center and"},{"name":"Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ranjit S.","family":"Bindra","sequence":"additional","affiliation":[{"name":"Department of Pathology and"},{"name":"Department of Therapeutic Radiology, Yale School of Medicine, New Haven, Connecticut, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7946-9255","authenticated-orcid":true,"given":"Raul","family":"Rabadan","sequence":"additional","affiliation":[{"name":"Departments of Systems Biology and Biomedical Informatics, Columbia University, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9031-7639","authenticated-orcid":true,"given":"Juan C.","family":"Vasquez","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dolores","family":"Hambardzumyan","sequence":"additional","affiliation":[{"name":"Departments of Oncological Sciences and Neurosurgery, The Tisch Cancer Institute and"},{"name":"Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2025,12,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1093\/nop\/npad061"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/noz150"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa043331"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2209-9"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.4161\/cc.9.1.10363"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1039\/c2ib20091k"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2011.12.004"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-09614-x"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/362652a0"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-020-02243-6"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1126\/science.8484121"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1111\/ene.12647"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2014-102284"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/ng0995-64"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80433-X"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01581-6"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1093\/noajnl\/vdad085"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1002\/cpz1.70097"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1126\/science.abn7570"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.18103\/mra.v13i9.6944"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-17-0151"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1126\/science.adg7492"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awaa382"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/noab106"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.bi.65.070196.000533"},{"issue":"21","key":"B26","first-page":"7934","article-title":"The distinct spectra of tumor-associated Apc mutations in mismatch repair-deficient Apc1638N mice define the roles of MSH3 and MSH6 in DNA repair and intestinal tumorigenesis","volume":"61","author":"Kuraguchi","year":"2001","journal-title":"Cancer Res"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-023-01499-4"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.gpb.2020.02.001"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2022-005059"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1126\/science.aau0447"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.138829"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.06.024"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1172\/JCI163802"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2024.09.007"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/nov172"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1002\/glia.23883"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.04.055"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1172\/JCI163447"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2009.11.009"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1101\/gad.14.8.994"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1998.16.12.3851"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-37361-8"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.3c06483"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14225494"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/noae257"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-14-3616"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1172\/JCI163451"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa043330"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/noac070"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1186\/s13014-023-02393-3"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.747690"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awz331"}],"container-title":["Journal of Clinical Investigation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.jci.org\/articles\/view\/195189\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T16:42:14Z","timestamp":1779208934000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.jci.org\/articles\/view\/195189"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,23]]},"references-count":52,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,3,16]]},"published-print":{"date-parts":[[2026,3,16]]}},"alternative-id":["10.1172\/JCI195189"],"URL":"https:\/\/doi.org\/10.1172\/jci195189","relation":{},"ISSN":["1558-8238"],"issn-type":[{"value":"1558-8238","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,23]]},"article-number":"e195189"}}