Single-cell and spatial omics reveals region-specific plasticity and therapeutic vulnerabilities in metastatic high-risk neuroblastoma.

Neuroblastoma, a pediatric cancer derived from sympathetic ganglia of the peripheral nervous system, frequently metastasizes, driving poor outcomes. Primary neuroblastomas are well-characterized, but the mechanisms underlying metastasis remain poorly understood. Here, by using single-cell and spatial multiomics, we identified that lymph node metastases in high-risk neuroblastomas display distinctive cellular heterogeneity and plasticity, marked by mesenchymal-like and stem-like states and heightened epithelial-to-mesenchymal transition activity compared to primary adrenal tumors. In addition, compared to primary adrenal masses, the metastatic niche display increased immunosuppressive myeloid programs, heightened immune checkpoint signaling, and lymphocyte exhaustion, which are indicative of immune evasion and dysfunction. Notably, metastatic neuroblastomas show elevated eIF4F translation machinery and XPO1 levels. Dual inhibition of eIF4A and XPO1 synergistically halted tumor growth and prolonged survival in xenograft models. Together, our multiomics studies reveal the molecular and cellular plasticity that contributes to therapy resistance and highlight exploitable therapeutic vulnerabilities in high-risk metastatic neuroblastomas.