Immunotherapy approaches for the treatment of relapsed or progressive medulloblastoma.

PURPOSE: Immunotherapy provides a novel and alternative treatment strategy to improve the outcomes in patients with refractory medulloblastoma. Two promising immunotherapies are immune checkpoint inhibitors (ICI) and chimeric antigen receptor (CAR) T-cells. In this review, we aim to summarize the available and investigational opportunities for ICI and CAR T-cell therapies, specifically for patients with refractory or relapsed medulloblastoma, tailored to their tumor molecular subtypes. METHODS: We searched the PubMed database and clinicaltrials.gov from January 2010 through October 2025 for studies evaluating treatments for patients with relapsed medulloblastoma. RESULTS: A point somatic mutation (r.3A>G) in U1, a non-coding snRNA, is found in two-thirds of patients with SHH-α tumors with TP53 mutations and in over 95% of SHH-δ tumors. The U1 mutation leads to altered splicing, potentially causing post-translational hypermutation. Accordingly, these tumors may be responsive to ICI. CAR T-cell therapies have shown promising results in patients with brain tumors. CAR T-cell therapies are designed to target universal tumor epitopes to improve their clinical testing feasibility. However, one challenge to achieving durable tumor control is the existence of treatment-resistant populations driven by intratumor heterogeneity. Therefore, we summarized the expression of available targets in specific medulloblastoma molecular groups to guide therapy selection. CONCLUSION: We provide a basic understanding of how the medulloblastoma molecular heterogeneity can serve as a window for ICI. Furthermore, we provide a summary of the current and future CAR-T cells being tested for the treatment of different refractory medulloblastoma based on their molecular subtypes.