The glymphatic system in oncology: from the perspective of a radiation oncologist

The brain and spinal cord, which constitute the central nervous system, were historically considered immune-privileged sites, as it was believed they lacked an equivalent to the systemic lymphatic system. However, in 2013, a pathway facilitating the clearance of waste products through the brain parenchyma via the perivascular space was proposed, garnering attention as the 'glymphatic system'. Similar to the systemic lymphatic system, the glymphatic system plays a critical role in immune responses and has been implicated not only in Alzheimer's disease and inflammatory brain disorders but also in conditions such as hydrocephalus and glaucoma, which are associated with cerebrospinal fluid circulation impairments. Recent studies have suggested that dysfunction of the glymphatic system may promote the progression of brain tumors and reduce the efficacy of immune responses and pharmacological therapies targeting tumors. Radiotherapy is a major treatment option for brain tumors; however, while it can enhance immune responses against tumors, it may also suppress these responses at the same time. Additionally, cranial irradiation has been suggested to impair the function of the glymphatic system. This review provides an overview of the structure and functional evaluation methods of the glymphatic system, summarizes the effects of its dysfunction on brain tumor treatment, and explores recent findings on the impact of radiation therapy on glymphatic system functioning. Lastly, it also explores the potential for radiation therapy strategies that account for their effects on the glymphatic system.