Overcoming temozolomide resistance in glioma: recent advances and mechanistic insights

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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Main Authors: Hengzeng Li, Yahui Wu, Yue Chen, Jinquan Lv, Chengkang Qu, Tingjie Mei, Yunfan Zheng, Cheng Ye, Feifei Li, Shuo Ge, Anhui Yao, Liyun Jia
Format: Article
Language:English
Published: BMC 2025-06-01
Series:Acta Neuropathologica Communications
Subjects:
Temozolomide
Glioma
Chemoresistance
Treatment strategies
Online Access:https://doi.org/10.1186/s40478-025-02046-4
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Summary: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.
ISSN:2051-5960

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