Erythrocyte-microglia crosstalk contributing to sex differences in pediatric brain tumorigenesis

Pediatric brain tumors are a leading cause of cancer-related morbidity and mortality, with limited treatment options and a male predominance across all ages of children and adolescents^1,2. However, the origins and underlying mechanisms of these sex differences in tumorigenesis remain elusive. Here, we use medulloblastoma (MB), the most common malignant brain tumor in children^3,4, as a model to demonstrate that sex-specific cell and organ interactions slow neural progenitor cell (NPC) differentiation, contributing to a higher incidence and poorer prognosis of MB in males. Single-cell transcriptome analyses of developing human and mouse cerebella, along with in vitro and in vivo validations, uncover intrinsic sexual dimorphisms in NPCs, regulated by microglia-mediated erythrophagocytosis and lipid transfer. In males, lower Glycophorin A (GYPA) expression in the erythrocyte membrane leads to increased cell damage and elevated microglial erythrophagocytosis. Male microglia also exhibit higher expression of Biliverdin Reductase B (BLVRB) and lower expression of ATP Binding Cassette 1 (ABCA1), which orchestrate bilirubin-lipid metabolism and reduce lipid transfer efficiency from microglia to NPCs, thereby slowing NPC differentiation and maturation in males compared to females. These sexual dimorphisms increase NPC vulnerabilities to oncogenic malignant transformation, contributing to the higher prevalence and metastasis of MB in males. Meta-analyses of clinical data reveal that neonatal hyperbilirubinemia (jaundice) caused by high levels of bilirubin, increases pediatric brain tumor risk. Collectively, these findings highlight the origins of sex differences in neurodevelopment and brain tumorigenesis, offering insights into early screening and prevention of pediatric brain tumors through targeted interventions addressing modifiable risk factors.