Comparative barriers to molecular therapy and immunotherapy in glioblastoma: A systematic review.

Background: Glioblastoma (GBM) remains refractory to molecular and immunotherapy, yet the barriers to each treatment class are often discussed together. We systematically compared the efficacy and delivery barriers reported for these approaches to clarify where their failure mechanisms overlap and diverge. Methods: A Preferred Reporting Items for Systematic reviews and Meta-Analyses-guided review of PubMed and ScienceDirect was conducted from database inception through April 4 Results: Eighty-two studies were included: 41 addressed both therapy classes, 34 immunotherapies only, and seven molecular therapies only. Blood-brain barrier (BBB)/blood-brain tumor barrier restriction and tumor heterogeneity were nearly universal (98.8% and 96.3%). Six barrier domains differed significantly across therapy groups. Immunosuppressive tumor microenvironment, T-cell exhaustion, low immunogenicity, and impaired central nervous system immune trafficking clustered with immunotherapy studies, whereas BBB efflux transport was concentrated in molecular therapy studies (85.7% vs. 2.9% in immunotherapy-only studies; Conclusion: Molecular therapy and immunotherapy in GBM share BBB restriction and heterogeneity but fail through distinct dominant mechanisms. Combination trials should be designed around both pharmacokinetic delivery barriers and immune-microenvironmental resistance, with patient selection matched to the biology being targeted.