Integrative single-cell and bulk transcriptome reveals DDR-related prognostic features of the medulloblastoma microenvironment

Dysregulation of the DNA damage response (DDR) has been implicated in medulloblastoma (MB) progression and therapeutic resistance. Using bulk transcriptomics, we developed and validated a novel DDR-based prognostic risk model for MB. High-risk patients exhibited poorer survival and immunosuppressive tumor microenvironments, yet were predicted to be more sensitive to PARP/Wee1 inhibitors and cisplatin. Furthermore, single-cell RNA-seq revealed that highly plastic, high-risk malignant clones heavily depend on DNA repair networks. Importantly, cell-cell communication analysis suggested enhanced MDK-NCL-mediated communication in high-risk malignant cells, which was associated with reduced cytotoxic T and NK cell infiltration and may contribute to an immunosuppressive microenvironment. In conclusion, this DDR-based evaluation system provides a potential approach for risk stratification in MB. Uncovering the MDK-NCL axis’s potential role in immune exclusion highlights promising therapeutic vulnerabilities for combined targeted and immunotherapeutic strategies.