基本原理：代谢的协同重编程主导神经母细胞瘤 (NB) 的进展。基于阐明代谢重编程的分子机制，开发个体化的NB风险预测方法和分层指导的治疗方案具有重要的临床意义。方法：通过基于机器学习的多步骤程序，在单细胞和代谢物通量维度上阐明了代谢重编程驱动的 NB 恶性进展的协同机制。随后，开发了一种有前途的代谢重编程相关预后特征（MPS）和基于 MPS 分层的个体化治疗方法，并使用临床前模型进一步独立验证。结果：MPS 鉴定的 MPS-I NB 显示出比 MPS-II 对应物显着更高的代谢重编程活性。与当前的临床特征相比，MPS 在预测预后方面表现出更高的准确性 [AUC：0.915 对比 0.657 (MYCN)、0.713（INSS 分期）和 0.808（INRG 分层）]。 AZD7762 和依托泊苷被确定为分别针对 MPS-I 和 II NB 的有效疗法。随后的生物学测试表明，AZD7762 显着抑制 MPS-I NB 细胞的生长、迁移和侵袭，比 MPS-II 细胞更有效。相反，依托泊苷对MPS-II NB细胞有更好的治疗效果。更令人鼓舞的是，AZD7762 和依托泊苷分别显着抑制 MPS-I 和 MPS-II 样本中的体内皮下肿瘤发生、增殖和肺转移。从而延长荷瘤小鼠的存活时间。从机制上讲，AZD7762 和依托泊苷分别通过线粒体依赖性途径诱导 MPS-I 和 MPS-II 细胞凋亡； MPS-I NB 通过谷氨酸代谢和乙酰辅酶 A 的成瘾来抵抗依托泊苷诱导的细胞凋亡。MPS-I NB 的进展受到多种代谢重编程驱动因素的推动，包括多药耐药、免疫抑制和促肿瘤炎症微环境。免疫学上，MPS-I NB 通过 MIF 和 THBS 信号通路抑制免疫细胞。在代谢上，MPS-I NB细胞的恶性增殖受到重编程的谷氨酸代谢、三羧酸循环、尿素循环等的显着支持。此外，MPS-I NB细胞表现出独特的促肿瘤发育谱系和自我通讯模式，如证据是随着发育和自我交流而激活的致癌信号通路增强。结论：本研究深入了解代谢重编程介导的 NB 恶性进展的分子机制。它还揭示了在新型精确风险预测方法指导下开发靶向药物的思路，这可能有助于显着改善 NB 的治疗策略。© 作者。

Rationale: Synergic reprogramming of metabolic dominates neuroblastoma (NB) progression. It is of great clinical implications to develop an individualized risk prognostication approach with stratification-guided therapeutic options for NB based on elucidating molecular mechanisms of metabolic reprogramming. Methods: With a machine learning-based multi-step program, the synergic mechanisms of metabolic reprogramming-driven malignant progression of NB were elucidated at single-cell and metabolite flux dimensions. Subsequently, a promising metabolic reprogramming-associated prognostic signature (MPS) and individualized therapeutic approaches based on MPS-stratification were developed and further validated independently using pre-clinical models. Results: MPS-identified MPS-I NB showed significantly higher activity of metabolic reprogramming than MPS-II counterparts. MPS demonstrated improved accuracy compared to current clinical characteristics [AUC: 0.915 vs. 0.657 (MYCN), 0.713 (INSS-stage), and 0.808 (INRG-stratification)] in predicting prognosis. AZD7762 and etoposide were identified as potent therapeutics against MPS-I and II NB, respectively. Subsequent biological tests revealed AZD7762 substantially inhibited growth, migration, and invasion of MPS-I NB cells, more effectively than that of MPS-II cells. Conversely, etoposide had better therapeutic effects on MPS-II NB cells. More encouragingly, AZD7762 and etoposide significantly inhibited in-vivo subcutaneous tumorigenesis, proliferation, and pulmonary metastasis in MPS-I and MPS-II samples, respectively; thereby prolonging survival of tumor-bearing mice. Mechanistically, AZD7762 and etoposide-induced apoptosis of the MPS-I and MPS-II cells, respectively, through mitochondria-dependent pathways; and MPS-I NB resisted etoposide-induced apoptosis by addiction of glutamate metabolism and acetyl coenzyme A. MPS-I NB progression was fueled by multiple metabolic reprogramming-driven factors including multidrug resistance, immunosuppressive and tumor-promoting inflammatory microenvironments. Immunologically, MPS-I NB suppressed immune cells via MIF and THBS signaling pathways. Metabolically, the malignant proliferation of MPS-I NB cells was remarkably supported by reprogrammed glutamate metabolism, tricarboxylic acid cycle, urea cycle, etc. Furthermore, MPS-I NB cells manifested a distinct tumor-promoting developmental lineage and self-communication patterns, as evidenced by enhanced oncogenic signaling pathways activated with development and self-communications. Conclusions: This study provides deep insights into the molecular mechanisms underlying metabolic reprogramming-mediated malignant progression of NB. It also sheds light on developing targeted medications guided by the novel precise risk prognostication approaches, which could contribute to a significantly improved therapeutic strategy for NB.© The author(s).