TFAP2D drives neuroblastoma progression: a disulfidptosis-fatty acid metabolism-based molecular subtyping and prognostic model.
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BACKGROUND: Neuroblastoma (NB) is recognized as the predominant extracranial malignant solid tumor in children and adolescent; the prognosis for high-risk patients remains poor. This limitation stems from its low mutational burden, an absence of antigen-presenting molecules, and vascular irregularities, which collectively impede immune cell infiltration, characterizing NB as a prototypical "cold tumor". Intriguingly, metabolic pathways, especially through a novel glucose-dependent cellular death mechanism termed disulfidptosis and fatty acid metabolism (FAM), are pivotal in modulating the tumor's energy dynamics and activating the tumor microenvironment (TME). Therefore, this study aims to explore the prognostic value and immunological implications of disulfidptosis-related fatty acid metabolism (DFAM) within the NB TME. METHODS: To elucidate the implications of DFAM within the NB TME, this research included 971 NB patients. By using weighted gene co-expression network analysis (WGCNA), we constructed a prognostic risk score model based on DFAM, aimed at enhancing prognostication accuracy and informing therapeutic choices. The biological role of TFAP2D was validated in SK-N-AS and SK-N-BE2 cells via Cell Counting Kit-8 (CCK-8) assay, wound healing, and Transwell. RESULTS: Two distinct novel molecular subtypes were identified, revealing the correlations between DFAM and clinical-pathological features, prognostic outcomes, and TME infiltration patterns. The DFAM risk score model was established as an independent prognostic factor, correlated with immune cell infiltration and immunotherapeutic response. A novel discovery was the inhibitory effect of TFAP2D downregulation in NB cells on cellular survival, migration, and invasion. CONCLUSIONS: This research demonstrates that the crosstalk between DFAM and immune cells plays an important role in forming the "cold" TME of NB. The construction of DFAM-related score and the identification of a novel molecular subtype significantly contribute to the evolution of immunotherapeutic strategies. Furthermore, the discovery of TFAP2D as a metabolic driver of tumor progression provides a potential target to disrupt the metabolic plasticity of high-risk NB.