Dual‑targeting therapeutic strategies for glioblastoma (Review)

Glioblastoma (GBM) is the most aggressive primary malignant tumour, owing to intratumoural heterogeneity, adaptive resistance, and an immunosuppressive microenvironment.Dual-targeting strategies aim to exploit complementary therapeutic vulnerabilities; however, their mechanisms of action and levels of supporting evidence vary considerably.The present narrative review evaluates single-molecule inhibitors, dual-antigen cellular therapies, oncolytic virus platforms, nanocarrier systems, and combination approaches directed against glioma stem-like and differentiated cellular states or spatially distinct tumour regions.Distinctions are made between molecular co-inhibition, dual-antigen recognition, coordinated drug delivery, and multimodal therapeutic strategies.Evidence derived from isocitrate dehydrogenase (IDH)-mutant glioma and other malignancies is considered separately from evidence in IDH-wildtype GBM.Vorasidenib (AG-881) inhibits both mutant IDH1 and mutant IDH2 within the same metabolic pathway; however, its clinical benefit in grade 2 IDH-mutant glioma does not demonstrate efficacy in GBM.Most alternative approaches remain at the preclinical stage, whereas early cellular therapy approaches have shown biological activity alongside significant limitations in response durability and neurological tolerability.Key challenges examined include clonal evolution, lineage plasticity, epigenetic and metabolic adaptation, patient stratification, and integration with radiotherapy.Translational priorities include confirming adequate drug exposure and engagement of both targets, identifying biologically appropriate patient populations, establishing tolerable treatment schedules, and streamlining manufacturing processes.Limiting tumour adaptation remains a testable therapeutic hypothesis rather than an established clinical outcome of dual targeting.Future progress will depend on research that links mechanistic complementarity to durable disease control and acceptable toxicity.Contents 1. Introduction 2. Therapeutic platforms 3. Complementary cellular and spatial dependencies 4. Integration with radiotherapy and radiosensitizers 5. Patient stratification and a precision framework 6. Resistance to dual-target interventions 7. Current challenges and prospects 8.