Translational Challenges and Strategies for Antibody Therapeutics in Glioblastoma

Glioblastoma (GBM) remains difficult to control. Monoclonal antibodies (mAbs) have transformed the treatment of several extracranial cancers, but they have not consistently improved survival in GBM. This narrative review examines the main biological and translational barriers to antibody-based therapy. It also evaluates strategies to overcome them. We reviewed preclinical, translational, and clinical evidence on antibody delivery, target stability, the tumor microenvironment, target discovery, and emerging antibody formats. Heterogeneous blood–brain and blood–tumor barriers produce uneven intratumoral exposure, especially at infiltrative margins. Spatial and temporal heterogeneity promotes antigen loss and treatment escape. Lymphocyte dysfunction, myeloid dominance, and suppressive vascular and metabolic programs further limit immune activity. Receptor-mediated transcytosis and focused ultrasound may improve delivery. Single-cell and spatial profiling, surfaceome and endocytome proteomics, longitudinal sampling, and causal inference may improve target selection. Depending on their design, antibody–drug conjugates (ADCs) can deliver cytotoxic payloads, whereas bispecific constructs can enable immune redirection, dual-target recognition, or receptor-mediated transport. However, clinical benefit remains limited by construct design, target accessibility, regional exposure, toxicity, and inadequate biomarker selection. Successful translation requires modality-specific alignment of exposure at the relevant site of action, target requirements, immune dependence, molecular design, and safety. Biomarker-guided patient selection, spatial pharmacokinetic and pharmacodynamic validation, and early evidence of clinical benefit are also essential.