Glioblastoma (GBM) remains one of the most treatment-resistant human malignancies, largely due to the interplay between disrupted fluid dynamics, immune evasion, and the structural complexity of the tumor microenvironment; in addition to these, treatment resistance is also driven by intratumoral heterogeneity, glioma stem cell persistence, hypoxia-induced metabolic and epigenetic plasticity, adaptive oncogenic signaling, and profound immunosuppression within the tumor microenvironment. Emerging evidence shows that dysfunction of the glymphatic system, mislocalization of aquaporin-4, and increased intracranial pressure compromise cerebrospinal fluid–interstitial fluid exchange and impair antigen drainage to meningeal lymphatics, thereby weakening immunosurveillance. GBM simultaneously remodels the blood–brain barrier into a heterogeneous and permeable blood–tumor barrier that restricts uniform drug penetration yet enables tumor progression. These alterations intersect with profound immunosuppression mediated by pericytes, tumor-associated macrophages, and hypoxic niches. Advances in imaging, including DCE-MRI, DTI-ALPS, CSF-tracing PET, and elastography, now allow in vivo characterization of glymphatic function and interstitial flow. Therapeutic strategies targeting the fluid-immune interface are rapidly expanding, including convection-enhanced delivery, intrathecal and intranasal approaches, focused ultrasound, nanoparticle systems, and lymphatic-modulating immunotherapies such as VEGF-C and STING agonists. Integrating barrier modulation with immunotherapy and nanomedicine holds promise for overcoming treatment resistance. Our review synthesizes the mechanistic, microenvironmental, and translational advances that position the glymphatic–immune axis as a new frontier in glioblastoma research.
Arroyo et al. (2026) studied this question.