Abstract 7880: Regulation of medulloblastoma growth and immune evasion by RNA methylation

Abstract Medulloblastoma (MB) is the most common malignant brain tumor in children. While advances in multimodal therapy have improved survival, many patients still succumb to the disease, and long-term survivors often experience debilitating neurological and developmental side effects. Post-transcriptional RNA modifications, collectively termed epitranscriptomics, have emerged as a critical regulator in cancer and development. N6 -methyladenosine (m6A) is the most prevalent eukaryotic RNA modification and regulates the stability and translation of modified mRNAs. The m6A methyltransferase, METTL3 promotes tumor growth and stemness in several cancers, yet its precise functions and therapeutic potential in MB remain poorly understood. Here, we investigated the role of RNA m6A modification in MB and identified METTL3 as an essential in vitro and in vivo dependency in genetically engineered mouse models of MB. RNAseq following METTL3 deletion revealed METTL3 target genes, the majority of which were upregulated. We further performed m6A profiling of MBs and overlapped it with RNAseq data to identify m6A dependent and downstream m6A independent targets of METTL3. Pathway enrichment analysis of METTL3 targets showed a strong enrichment for genes associated with innate immune response, antiviral response, RNA processing and cholesterol biosynthesis among others. In addition, METTL3 depletion enhanced the immunogenicity of MB tumors. Pharmacological inhibition of m6A by STM9201 in multiple MB cell lines decreased global mRNA m6A levels and the cell viability in a dose-dependent manner. Moreover, oral administration of STM9201 in MB mouse models suppressed tumor growth. Ongoing mechanistic studies aim to delineate the cell-intrinsic and cell-extrinsic pathways through which METTL3 regulates MB progression and immune response. Citation Format: Deobrat Dixit, Robert Wechsler-Reya. Regulation of medulloblastoma growth and immune evasion by RNA methylation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7880.