Overcoming temozolomide resistance in glioma: recent advances and mechanistic insights
Abstract Temozolomide (TMZ) remains the cornerstone chemotherapy for glioma, yet intrinsic and acquired resistance mechanisms significantly limit its clinical effectiveness. This review summarizes the multifaceted molecular pathways contributing to TMZ resistance, including enhanced DNA repair mecha...
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| Format: | Article |
| Language: | English |
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BMC
2025-06-01
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| Series: | Acta Neuropathologica Communications |
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| Online Access: | https://doi.org/10.1186/s40478-025-02046-4 |
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| author | Hengzeng Li Yahui Wu Yue Chen Jinquan Lv Chengkang Qu Tingjie Mei Yunfan Zheng Cheng Ye Feifei Li Shuo Ge Anhui Yao Liyun Jia |
| author_facet | Hengzeng Li Yahui Wu Yue Chen Jinquan Lv Chengkang Qu Tingjie Mei Yunfan Zheng Cheng Ye Feifei Li Shuo Ge Anhui Yao Liyun Jia |
| author_sort | Hengzeng Li |
| collection | DOAJ |
| description | Abstract Temozolomide (TMZ) remains the cornerstone chemotherapy for glioma, yet intrinsic and acquired resistance mechanisms significantly limit its clinical effectiveness. This review summarizes the multifaceted molecular pathways contributing to TMZ resistance, including enhanced DNA repair mechanisms such as O6-methylguanine-DNA methyltransferase (MGMT), mismatch repair (MMR), and base excision repair (BER). Additional resistance factors include genetic mutations that affect the drug response, dysregulated non-coding RNAs (miRNAs, lncRNAs, and circRNAs), glioma stem cells (GSCs), cytoprotective autophagy, an immunosuppressive tumor microenvironment (TME), altered signaling pathways, and active drug efflux transporters. Recent advancements to overcome these resistance mechanisms, including enhancing TMZ bioavailability through nanoparticle-based delivery systems and the inhibition of efflux transporters, have been explored. Novel therapeutic approaches that target DNA repair pathways and manipulate autophagy are highlighted. Immunotherapeutic interventions reversing immune suppression and metabolic strategies targeting tumor metabolism offer additional avenues. Emerging therapies such as CRISPR-based gene editing, phytochemical combinations, repurposed drugs, and novel TMZ analogs designed to bypass MGMT-mediated resistance are also discussed. This review highlights current developments and identifies emerging areas, with the goals of enhancing clinical outcomes and prolonging survival for glioma patients. |
| format | Article |
| id | doaj-art-7abff4daaf174659bb9825d8587906d8 |
| institution | DOAJ |
| issn | 2051-5960 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj-art-7abff4daaf174659bb9825d8587906d82025-08-20T03:10:20ZengBMCActa Neuropathologica Communications2051-59602025-06-0113113810.1186/s40478-025-02046-4Overcoming temozolomide resistance in glioma: recent advances and mechanistic insightsHengzeng Li0Yahui Wu1Yue Chen2Jinquan Lv3Chengkang Qu4Tingjie Mei5Yunfan Zheng6Cheng Ye7Feifei Li8Shuo Ge9Anhui Yao10Liyun Jia11Department of Medical Genetics & Cell Biology, School of Basic Medical Sciences, Zhengzhou UniversityThe First Clinical School of Medicine, Zhengzhou UniversityDepartment of Medical Genetics & Cell Biology, School of Basic Medical Sciences, Zhengzhou UniversityDepartment of Medical Genetics & Cell Biology, School of Basic Medical Sciences, Zhengzhou UniversityThe First Clinical School of Medicine, Zhengzhou UniversityDepartment of Medical Genetics & Cell Biology, School of Basic Medical Sciences, Zhengzhou UniversityThe First Clinical School of Medicine, Zhengzhou UniversityThe First Clinical School of Medicine, Zhengzhou UniversityDepartment of Medical Genetics & Cell Biology, School of Basic Medical Sciences, Zhengzhou UniversityDepartment of Medical Genetics & Cell Biology, School of Basic Medical Sciences, Zhengzhou UniversityDepartment of Neurosurgery, 988th Hospital of Joint Logistic Support Force of PLADepartment of Medical Genetics & Cell Biology, School of Basic Medical Sciences, Zhengzhou UniversityAbstract Temozolomide (TMZ) remains the cornerstone chemotherapy for glioma, yet intrinsic and acquired resistance mechanisms significantly limit its clinical effectiveness. This review summarizes the multifaceted molecular pathways contributing to TMZ resistance, including enhanced DNA repair mechanisms such as O6-methylguanine-DNA methyltransferase (MGMT), mismatch repair (MMR), and base excision repair (BER). Additional resistance factors include genetic mutations that affect the drug response, dysregulated non-coding RNAs (miRNAs, lncRNAs, and circRNAs), glioma stem cells (GSCs), cytoprotective autophagy, an immunosuppressive tumor microenvironment (TME), altered signaling pathways, and active drug efflux transporters. Recent advancements to overcome these resistance mechanisms, including enhancing TMZ bioavailability through nanoparticle-based delivery systems and the inhibition of efflux transporters, have been explored. Novel therapeutic approaches that target DNA repair pathways and manipulate autophagy are highlighted. Immunotherapeutic interventions reversing immune suppression and metabolic strategies targeting tumor metabolism offer additional avenues. Emerging therapies such as CRISPR-based gene editing, phytochemical combinations, repurposed drugs, and novel TMZ analogs designed to bypass MGMT-mediated resistance are also discussed. This review highlights current developments and identifies emerging areas, with the goals of enhancing clinical outcomes and prolonging survival for glioma patients.https://doi.org/10.1186/s40478-025-02046-4TemozolomideGliomaChemoresistanceTreatment strategies |
| spellingShingle | Hengzeng Li Yahui Wu Yue Chen Jinquan Lv Chengkang Qu Tingjie Mei Yunfan Zheng Cheng Ye Feifei Li Shuo Ge Anhui Yao Liyun Jia Overcoming temozolomide resistance in glioma: recent advances and mechanistic insights Acta Neuropathologica Communications Temozolomide Glioma Chemoresistance Treatment strategies |
| title | Overcoming temozolomide resistance in glioma: recent advances and mechanistic insights |
| title_full | Overcoming temozolomide resistance in glioma: recent advances and mechanistic insights |
| title_fullStr | Overcoming temozolomide resistance in glioma: recent advances and mechanistic insights |
| title_full_unstemmed | Overcoming temozolomide resistance in glioma: recent advances and mechanistic insights |
| title_short | Overcoming temozolomide resistance in glioma: recent advances and mechanistic insights |
| title_sort | overcoming temozolomide resistance in glioma recent advances and mechanistic insights |
| topic | Temozolomide Glioma Chemoresistance Treatment strategies |
| url | https://doi.org/10.1186/s40478-025-02046-4 |
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