{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T19:53:58Z","timestamp":1789588438287,"version":"build-2803163510"},"reference-count":357,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T00:00:00Z","timestamp":1772064000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Federal Medical Biological Agency of the Russian Federation","award":["388-00087-26-01"],"award-info":[{"award-number":["388-00087-26-01"]}]},{"DOI":"10.13039\/501100017638","name":"Ministry of Health of the Russian Federation","doi-asserted-by":"crossref","award":["124021400005-3"],"award-info":[{"award-number":["124021400005-3"]}],"id":[{"id":"10.13039\/501100017638","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and remains highly lethal, with median overall survival rarely exceeding 15 months despite maximal surgical resection, radiotherapy, and temozolomide-based chemotherapy. Therapeutic resistance in GBM is driven by intrinsic tumor cell adaptations, extensive inter- and intratumoral heterogeneity, and microenvironmental constraints. Key mechanisms include enhanced DNA repair, disrupted apoptosis, pathway redundancy, altered drug metabolism, oxidative stress tolerance, and glioblastoma stem cell\u2013mediated plasticity. In vivo, resistance is reinforced by the blood\u2013brain barrier, hypoxia, stromal and immune interactions, and selective expansion of therapy-resistant clones. Current strategies to overcome resistance target DNA repair, oxidative stress, autophagy, and metabolic vulnerabilities; however, their efficacy is limited by tumor heterogeneity and delivery barriers. Precision oncology approaches are hampered by a paucity of validated predictive biomarkers, leaving many patients without actionable targets. Ex vivo functional drug sensitivity testing of patient-derived tumor cells offers a complementary strategy, directly assessing individual tumor responses and guiding rational combination therapies. This review highlights the molecular and cellular mechanisms underlying chemoresistance in GBM, examines emerging therapeutic strategies, and explores the potential of integrating personalized, functionally guided approaches into clinical management. Addressing GBM\u2019s profound heterogeneity and adaptive plasticity is essential to improving outcomes in this aggressive and refractory malignancy.<\/jats:p>","DOI":"10.3390\/ijms27052207","type":"journal-article","created":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T13:58:03Z","timestamp":1772114283000},"page":"2207","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Overcoming Chemoresistance in Glioblastoma: Mechanisms, Therapeutic Strategies, and Functional Precision Medicine"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9340-2636","authenticated-orcid":false,"given":"Maria Y.","family":"Kordyukova","sequence":"first","affiliation":[{"name":"Federal Center of Brain Research and Neurotechnologies, Federal Medical and Biological Agency, 117513 Moscow, 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Russian National, Research Medical University, Ministry of Health of the Russian Federation, 117513 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeriya I.","family":"Meshcheryakova","sequence":"additional","affiliation":[{"name":"Laboratory of Synthetic Neurotechnologies, Pirogov Russian National, Research Medical University, Ministry of Health of the Russian Federation, 117513 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilya V.","family":"Grigoriev","sequence":"additional","affiliation":[{"name":"Federal Center of Brain Research and Neurotechnologies, Federal Medical and Biological Agency, 117513 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilya V.","family":"Senko","sequence":"additional","affiliation":[{"name":"Federal Center of Brain Research and Neurotechnologies, Federal Medical and Biological Agency, 117513 Moscow, Russia"},{"name":"Laboratory of Synthetic 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Russian Federation, 117513 Moscow, Russia"},{"name":"Life Improvement by Future Technologies (LIFT) Center, 121205 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"iv1","DOI":"10.1093\/neuonc\/noaf194","article-title":"CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2018\u20132022","volume":"27","author":"Price","year":"2025","journal-title":"Neuro Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1093\/neuonc\/noab106","article-title":"The 2021 WHO Classification of Tumors of the Central Nervous System: A Summary","volume":"23","author":"Louis","year":"2021","journal-title":"Neuro 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