THE GLYMPHATIC SYSTEM IN GLIOBLASTOMA: PROMISES AND PITFALLS

Abstract AIMS The glymphatic system, comprising perivascular spaces, astrocytic aquaporin-4 (AQP4) water channels, cere- brospinal fluid (CSF) and interstitial fluid (ISF), plays a crucial role in waste clearance, fluid homeostasis, and immune surveillance. Recognised as the brain’s “fourth circulation,” it has been implicated in several neurolog- ical diseases, although its role in glioblastoma remains poorly understood. Here we evaluate the interactions between glioblastoma and the glymphatic system, their implications for tumour progression, immune evasion, and drug delivery, and potential therapeutic strategies targeting glymphatic pathways. METHODS A systematic review of clinical and experimental studies was conducted to assess glymphatic dysfunction in glioblastoma. Key areas examined include its role in tumour spread, oedema formation, CSF dynamics, immune response and glymphatic-mediated drug delivery. The review also explores emerging therapeutic strategies targeting AQP4 and glymphatic flow to enhance immunotherapy and chemotherapy efficacy. RESULTS Glioblastoma disrupts glymphatic function by impairing its outflow as demonstrated using advanced MRI tech- niques, altering AQP4 polarisation, and increasing interstitial pressure. This dysfunction may explain the paradox of significant peritumoral oedema without hydrocephalus and the limited CSF-borne dissemination of glioblastoma. While glymphatic pathways facilitate cellular migration, including tumour infiltration along perivascular spaces, the “go or grow” hypothesis suggests that the most motile glioblastoma cells evade con- ventional therapies. Enhancing glymphatic flow could improve immune cell trafficking and synergise with immunotherapy. CONCLUSION The glymphatic system represents a promising yet complex target in glioblastoma therapy. Further mechanistic studies are needed to determine whether modulating glymphatic function can enhance treatment efficacy or inadvertently facilitate tumour invasion