MYCN-driven metabolic remodelling of the tumour microenvironment in neuroblastoma: implications for stromal biology and CAF heterogeneity.

Abstract

Neuroblastoma (NB) is the most common extracranial solid tumour of childhood and remains a leading cause of paediatric cancer mortality, particularly in high-risk disease driven by MYCN amplification. Although MYCN is a central oncogenic driver, its role as a transcription factor has limited direct therapeutic targeting, shifting attention toward downstream metabolic and microenvironmental dependencies. Increasing evidence indicates that MYCN-driven metabolic rewiring extends beyond tumour-intrinsic processes to reshape the tumour microenvironment (TME), influencing immune composition and stromal dynamics. Recent advances in single-cell and spatial profiling technologies have revealed substantial heterogeneity within the NB TME, highlighting complex interactions between tumour cells, immune populations, and stromal components. Among these, cancer-associated fibroblasts (CAFs) have emerged as key regulators of extracellular matrix architecture, immune modulation, and metabolic crosstalk. However, CAF identity, functional diversity, and lineage relationships in NB remain incompletely defined, with significant overlap between tumour-intrinsic mesenchymal programs and stromal fibroblast signatures. In this review, we synthesise current understanding of MYCN-driven metabolic reprogramming and its impact on CAF heterogeneity and immune regulation. We integrate insights from adult cancers with emerging data in NB to critically evaluate CAF functional states, including inflammatory and myofibroblastic programs, and their roles in shaping tumour progression, immune exclusion, and therapeutic response. By framing NB as a MYCN-remodelled tumour ecosystem, this review identifies key knowledge gaps in stromal biology and highlights the need to resolve CAF heterogeneity and tumour-stroma interactions. These insights have broader implications for MYC-driven malignancies and support the development of integrated therapeutic strategies targeting both tumour cells and their supportive microenvironment.