Therapeutic approaches for targeting the pediatric brain tumor microenvironment

Central nervous system (CNS) tumors are the most frequent solid malignant tumors in pediatric patients and are the leading cause of tumor-related death in children. Treatment for this heterogeneous group of tumors consists of various combinations of safe maximal surgical resection, chemotherapy, and radiation therapy which offer a cure for some children but often cause debilitating adverse late effects in others. While therapies targeting the tumor microenvironment (TME) like immune checkpoint inhibition (ICI) have been successful in treating some cancers, these therapies failed to exhibit treatment efficacy in the majority of pediatric brain tumors in the clinic. Importantly, the pediatric TME is unique and distinct from adult brain tumors and designing therapies to effectively target these tumors requires understanding the unique biology of pediatric brain tumors and the use of translational models that recapitulate the TME. Here we describe the TME of medulloblastoma (MB) and diffuse midline glioma (DMG), specifically diffuse intrinsic pontine glioma (DIPG), and further present the current drug delivery approaches and clinical administration routes targeting the TME in these tumors, including preclinical and clinical studies.Graphical AbstractConsiderations for developing therapeutic approaches to target pediatric brain tumor microenvironment including drug delivery carriers, CNS specific delivery routes, and clinically relevant models for preclinical evaluation 1.