Circumventing vascular barriers for effective immunotherapy in brain tumors – focus on glioblastoma

Abstract Blood vessels play a fundamental and unique role in brain tumor pathogenesis, including by mediating interactions with the peripheral immune system. Despite this intimate connection, endogenous immune surveillance and multiple modalities of immunotherapy have thus far exerted relatively little impact on disease progression and patient survival in high-grade brain tumors, such as glioblastoma (GBM). This applies to both adults and children, where complex vascular processes have emerged as possible actionable targets beyond anti-angiogenesis. Indeed, vascular responses in GBM include angiogenic, non-angiogenic (cooption, vasectasia), and angiocrine interactions mediated by soluble factors and extracellular vesicles (EVs). It is still poorly understood why immune cells are excluded from the GBM tumor microenvironment and what barriers may operate at the immune-vascular interface which could be modified to improve immunotherapy outcomes. The emerging research directions include efforts to overcome the immune cell exclusion, defining molecular hallmarks of treatment susceptibility in subsets of patients, assessing different immune effectors, and rational temporal scheduling of immunotherapy administration relative to the effects of cytoreductive treatments. It is suggested that experimental insights into the interplay between vascular and immune cell compartments may serve as hypothesis-generating material for future clinical studies in GBM.