Understanding resistance in glioblastoma: insights into personalized and targeted therapeutic strategies

Glioblastoma multiforme (GBM) is the most common and aggressive primary malignant brain tumor. Despite combined treatments, including surgical removal followed by radiation and chemotherapy, the prognosis remains poor. Even with temozolomide, the current standard for GBM treatment, the disease is still incurable because of GBM's highly invasive nature and resistance to therapy. This review examines the contributions of key DNA repair pathways, including O6-methylguanine-DNA methyltransferase, base excision repair, and homologous recombination, to the resolution of DNA lesions induced by therapy. It also highlights emerging molecular therapeutic targets that exploit synthetic lethality to enhance treatment efficacy. In addition, the review explores other determinants of GBM resistance, such as oncogenic genetic mutations, the tumorigenic glioma stem cells (GSCs), metabolic reprogramming within the tumor microenvironment that promotes immune evasion, and the restrictive nature of the blood-brain barrier, which limits effective drug intratumoral concentrations. Finally, we discuss patient-specific immunotherapeutic strategies, including chimeric antigen receptor T (CAR-T) cell therapy and personalized cancer vaccines, which hold promise for improving survival outcomes across different GBM subtypes. Advances in multi-omics profiling and machine learning are reshaping opportunities for personalized therapy in GBM. Integrating WES, RNA-seq, and HLA typing enables tailored immunotherapies, while AI-driven antibody design accelerates the development of GSC-targeting candidates. Yet translation remains hindered by GBM's heterogeneity, limited patient availability, and disparities in trial participation. Progress will require combining mechanistic tumor profiling with computational design approaches within more inclusive clinical trials to advance truly personalized and effective GBM treatment.