2025/04/14 by Wenbao Yu, Rumeysa Biyik‐Sit, Yasin Uzun +23 · 1 voice · 1 citation
Medicine · Immunology and Microbiology · #Neuroblastoma Research and Treatments #Immune cells in cancer #Glioma Diagnosis and Treatment
paper · pdf · doi:10.1038/s41588-025-02158-6
openalex publication_date 2025/04/14 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/25
High-risk neuroblastoma, a leading cause of pediatric cancer mortality, exhibits substantial intratumoral heterogeneity, contributing to therapeutic resistance. To understand tumor microenvironment evolution during therapy, we longitudinally profiled 22 patients with high-risk neuroblastoma before and after induction chemotherapy using single-nucleus RNA and ATAC sequencing and whole-genome sequencing. This revealed profound shifts in tumor and immune cell subpopulations after therapy and identified enhancer-driven transcriptional regulators of neuroblastoma neoplastic states. Poor outcome correlated with proliferative and metabolically active neoplastic states, whereas more differentiated neuronal-like states predicted better prognosis. Proportions of mesenchymal neoplastic cells increased after therapy and a high proportion correlated with a poorer chemotherapy response. Macrophages significantly expanded towards pro-angiogenic, immunosuppressive and metabolic phenotypes. We identified paracrine signaling networks and validated the HB-EGF-ERBB4 axis between macrophage and neoplastic subsets, which promoted tumor growth through the induction of ERK signaling. These findings collectively reveal intrinsic and extrinsic regulators of therapy response in high-risk neuroblastoma.