Comparative barriers to molecular therapy and immunotherapy in glioblastoma: A systematic review
Haneen A. Salih, Ali Z. Al-Saffar, Zaid Nsaif Abbas, Samer S. HozBackground:
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 th , 2026. Eligible adult GBM studies addressing molecular therapy, immunotherapy, or both were screened and categorized by therapy type. Ten predefined barrier domains were coded as present or absent. Barrier frequencies were compared across groups using Chi-square tests, followed by Fisher’s exact tests for pairwise comparisons when appropriate.
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; P < 0.001). Intrinsic or adaptive resistance was universal in molecular therapy and combined-therapy studies but lower in immunotherapy-only sources (73.5%; P < 0.001).
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.