Pediatric high-grade gliomas (pHGGs), particularly diffuse midline gliomas (DMGs), are among the most lethal brain tumors due to poor survival and resistance to therapies. DMGs possess a distinct genetic profile, primarily driven by hallmark mutations such as H3K27M, ACVR1, and PDGFRA mutations/amplifications and TP53 inactivation, all of which contribute to tumor biology and therapeutic resistance. Developing physiologically relevant preclinical models that replicate both tumor biology and the tumor microenvironment (TME) is critical for advancing effective treatments. This review highlights recent progress in in vitro, ex vivo, and in vivo models, including patient-derived brain organoids, genetically engineered mouse models (GEMMs), and region-specific midline organoids incorporating SHH, BMP, and FGF2/8/19 signaling to model pontine gliomas. Key genetic alterations can now be introduced using lipofectamine-mediated transfection, PiggyBac plasmid systems, and CRISPR-Cas9, allowing the precise study of tumor initiation, progression, and therapy resistance. These models enable the investigation of TME interactions, including immune responses, neuronal infiltration, and therapeutic vulnerabilities. Future advancements involve developing immune-competent organoids, integrating vascularized networks, and applying multi-omics platforms like single-cell RNA sequencing and spatial transcriptomics to dissect tumor heterogeneity and lineage-specific vulnerabilities. These innovative approaches aim to enhance drug screening, identify new therapeutic targets, and accelerate personalized treatments for pediatric gliomas.
儿童高级别胶质瘤（pHGGs），尤其是弥漫性中线胶质瘤（DMGs），因其生存率低且对治疗具有抵抗性，属于最具致命性的脑肿瘤之一。DMGs具有独特的遗传特征，主要由H3K27M、ACVR1和PDGFRA突变/扩增以及TP53失活等标志性突变驱动，这些突变共同影响肿瘤生物学特性及治疗抵抗性。开发能够同时模拟肿瘤生物学和肿瘤微环境（TME）的生理相关性临床前模型，对于推进有效治疗至关重要。本综述重点介绍了体外、离体和体内模型的最新进展，包括患者来源的脑类器官、基因工程小鼠模型（GEMMs），以及通过整合SHH、BMP和FGF2/8/19信号通路来模拟脑桥胶质瘤的区域特异性中线类器官。目前可通过脂质体介导的转染、PiggyBac质粒系统和CRISPR-Cas9技术引入关键遗传改变，从而精确研究肿瘤的发生、进展和治疗抵抗机制。这些模型有助于探究TME相互作用，包括免疫反应、神经元浸润及治疗薄弱环节。未来发展方向包括开发具有免疫活性的类器官、整合血管化网络，并应用单细胞RNA测序和空间转录组学等多组学平台，以解析肿瘤异质性和谱系特异性弱点。这些创新方法旨在加强药物筛选、发现新治疗靶点，并加速儿童胶质瘤的个性化治疗进程。
肿瘤(癌症)患者之家