Chimeric antigen receptor T cell therapy for glioblastoma: overcoming current barriers and strategies to enhance efficacy for therapeutic implications.

Glioblastoma (GBM) is a highly malignant primary brain tumor, characterized by limited therapeutic options and poor survival outcomes. Nevertheless, its treatment is significantly hampered by the immunosuppressive tumor microenvironment, tumor antigen heterogeneity, the risks of antigen escape, and on-target/off-tumor toxicity. To address these barriers, chimeric antigen receptor (CAR-T) cell therapy has emerged as a promising immunotherapeutic approach, showing potential in early clinical trials targeting epidermal growth factor receptor variant III (EGFRvIII), human epidermal growth factor receptor 2 (HER2), and interleukin-13 receptor alpha 2 (IL13Rα2). However, the efficacy of CAR-T cells for GBM is constrained by their limited persistence, tumor infiltration, and functional activity. This review therefore highlights key engineering methods to modify CAR-T cells for GBM, including enhancing resistance to immunosuppressive cytokines through transforming growth factor-beta (TGF-β) inhibition or signal conversion, blocking inhibitory checkpoints with gene editing, promoting tumor infiltration by chemokine receptor engineering or localized delivery, improving viability via cytokine support, delaying T cell exhaustion through modulation of exhaustion drivers, metabolic reprogramming to sustain function in nutrient-poor environments, and enriching memory phenotypes for long-term persistence. Future studies are required to develop multimodal approaches that combine next-generation CAR designs with enhanced delivery methods to simultaneously target multiple resistance pathways. Accordingly, this review aims to provide knowledge and pathways to overcome the pharmacological obstacles that have hindered CAR-T cell success in GBM, creating a roadmap for future research and clinical development.