Transcriptional programs dictating tumor cell fate decisions in neuroblastoma lymph node metastasis [single-cell multiomics]

Neuroblastoma, a deadly pediatric cancer from the sympathetic ganglia of the peripheral nervous system, frequently metastasizes, driving poor outcomes in high-risk cases. While primary tumors are well-characterized, the cellular and molecular dynamics of metastasis remain poorly understood. Here, we employed single-cell multi-omics and spatial transcriptomics to profile lymph node metastases in high-risk neuroblastoma compared to primary adrenal masses. We found that lymph node metastases displayed unique cellular heterogeneity and plasticity marked by a shift toward mesenchymal-like and cancer stem cell states, with enriched epithelial-to-mesenchymal transition (EMT) programs. Lymph node metastatic niche exhibited altered tumor microenvironment dynamics, characterized by increased immunosuppressive myeloid subsets, heightened immune checkpoint signaling and lymphocyte exhaustion, indicative of immune evasion and dysfunction. Our multi-omics studies reveal distinct features of high-risk neuroblastoma that contribute to metastasis and therapy resistance, pointing to potential therapeutic vulnerabilities of the aggressive metastatic disease.