{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T22:13:41Z","timestamp":1792188821815,"version":"4.4.0"},"reference-count":154,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2021,2,24]],"date-time":"2021-02-24T00:00:00Z","timestamp":1614124800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["CA221747"],"award-info":[{"award-number":["CA221747"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["CA234799"],"award-info":[{"award-number":["CA234799"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["NS093843"],"award-info":[{"award-number":["NS093843"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["NS095634"],"award-info":[{"award-number":["NS095634"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["NS115403"],"award-info":[{"award-number":["NS115403"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The Lou and Jean Malnati Brain Tumor Institute at Northwestern Medcine","award":["10031379"],"award-info":[{"award-number":["10031379"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Glioblastoma (GBM) is the most lethal type of primary brain cancer. Standard care using chemo- and radio-therapy modestly increases the overall survival of patients; however, recurrence is inevitable, due to treatment resistance and lack of response to targeted therapies. GBM therapy resistance has been attributed to several extrinsic and intrinsic factors which affect the dynamics of tumor evolution and physiology thus creating clinical challenges. Tumor-intrinsic factors such as tumor heterogeneity, hypermutation, altered metabolomics and oncologically activated alternative splicing pathways change the tumor landscape to facilitate therapy failure and tumor progression. Moreover, tumor-extrinsic factors such as hypoxia and an immune-suppressive tumor microenvironment (TME) are the chief causes of immunotherapy failure in GBM. Amid the success of immunotherapy in other cancers, GBM has occurred as a model of resistance, thus focusing current efforts on not only alleviating the immunotolerance but also evading the escape mechanisms of tumor cells to therapy, caused by inter- and intra-tumoral heterogeneity. Here we review the various mechanisms of therapy resistance in GBM, caused by the continuously evolving tumor dynamics as well as the complex TME, which cumulatively contribute to GBM malignancy and therapy failure; in an attempt to understand and identify effective therapies for recurrent GBM.<\/jats:p>","DOI":"10.3390\/cells10030484","type":"journal-article","created":{"date-parts":[[2021,2,24]],"date-time":"2021-02-24T20:53:21Z","timestamp":1614200001000},"page":"484","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":169,"title":["The Many Facets of Therapy Resistance and Tumor Recurrence in Glioblastoma"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2807-2551","authenticated-orcid":false,"given":"Anshika","family":"Goenka","sequence":"first","affiliation":[{"name":"The Robert H. Lurie Comprehensive Cancer Center, The Ken &amp; Ruth Davee Department of Neurology, The Lou and Jean Malnati Brain Tumor Institute, Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2881-7691","authenticated-orcid":false,"given":"Deanna","family":"Tiek","sequence":"additional","affiliation":[{"name":"The Robert H. Lurie Comprehensive Cancer Center, The Ken &amp; Ruth Davee Department of Neurology, The Lou and Jean Malnati Brain Tumor Institute, Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3171-4300","authenticated-orcid":false,"given":"Xiao","family":"Song","sequence":"additional","affiliation":[{"name":"The Robert H. Lurie Comprehensive Cancer Center, The Ken &amp; Ruth Davee Department of Neurology, The Lou and Jean Malnati Brain Tumor Institute, Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1441-3554","authenticated-orcid":false,"given":"Tianzhi","family":"Huang","sequence":"additional","affiliation":[{"name":"The Robert H. Lurie Comprehensive Cancer Center, The Ken &amp; Ruth Davee Department of Neurology, The Lou and Jean Malnati Brain Tumor Institute, Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9882-4053","authenticated-orcid":false,"given":"Bo","family":"Hu","sequence":"additional","affiliation":[{"name":"The Robert H. Lurie Comprehensive Cancer Center, The Ken &amp; Ruth Davee Department of Neurology, The Lou and Jean Malnati Brain Tumor Institute, Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1737-0588","authenticated-orcid":false,"given":"Shi-Yuan","family":"Cheng","sequence":"additional","affiliation":[{"name":"The Robert H. Lurie Comprehensive Cancer Center, The Ken &amp; Ruth Davee Department of Neurology, The Lou and Jean Malnati Brain Tumor Institute, Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1097\/PAP.0000000000000048","article-title":"Molecular pathways in gliomagenesis and their relevance to neuropathologic diagnosis","volume":"22","author":"Appin","year":"2015","journal-title":"Adv. Anat. Pathol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/nrclinonc.2016.204","article-title":"Advances in the molecular genetics of gliomas-implications for classification and therapy","volume":"14","author":"Reifenberger","year":"2017","journal-title":"Nat. Rev. Clin. 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