LAUSR

Simple Summary The current treatment options for medulloblastoma, the most common malignant childhood brain cancer, are associated with many negative side effects and toxicities. Therefore, novel treatment options are needed that target the tumor without affecting the healthy tissue. Medulloblastoma tumors consist of a wide variety of cell types and extracellular components that make up the microenvironment of the tumor. This tumor microenvironment influences the development, progression, and relapse of medulloblastoma through different cell–cell and cell–extracellular matrix interactions. Obtaining insights into these interactions will help with gaining a better understanding of this malignancy. Additionally, it could support the search for new targets of treatments directed at components of the tumor microenvironment. Abstract Medulloblastoma (MB) is a heterogeneous disease in which survival is highly affected by the underlying subgroup-specific characteristics. Although the current treatment modalities have increased the overall survival rates of MB up to 70–80%, MB remains a major cause of cancer-related mortality among children. This indicates that novel therapeutic approaches against MB are needed. New promising treatment options comprise the targeting of cells and components of the tumor microenvironment (TME). The TME of MB consists of an intricate multicellular network of tumor cells, progenitor cells, astrocytes, neurons, supporting stromal cells, microglia, immune cells, extracellular matrix components, and vasculature systems. In this review, we will discuss all the different components of the MB TME and their role in MB initiation, progression, metastasis, and relapse. Additionally, we briefly introduce the effect that age plays on the TME of brain malignancies and discuss the MB subgroup-specific differences in TME components and how all of these variations could affect the progression of MB. Finally, we highlight the TME-directed treatments, in which we will focus on therapies that are being evaluated in clinical trials.