Shah Siddharth, Lucke-Wold Brandon
Department of Neurosurgery, University of Florida, Gainesville, FL 32608, USA; Department of Neurosurgery, RCSM Government Medical College, Kolhapur, Maharashtra, India.
Department of Neurosurgery, University of Florida, Gainesville, FL 32608, USA.
World Neurosurg. 2025 Jun 4:124142. doi: 10.1016/j.wneu.2025.124142.
Glioblastoma (GBM) is an aggressive primary brain tumor with poor prognosis despite multimodal treatment. While prior research focused on tumor cell evolution, growing evidence highlights the tumor microenvironment (TME) as a key driver of therapeutic resistance and disease progression. Understanding GBM-TME interactions is crucial for identifying novel therapeutic targets.
A comprehensive literature search was conducted in PubMed, Embase, and Web of Science for English-language studies up to December 2024. Relevant observational studies, clinical trials, meta-analyses, and reviews were analyzed to evaluate cell-intrinsic and cell-extrinsic mechanisms driving GBM progression and treatment resistance.
Emerging evidence suggests that phenotypic plasticity, rather than DNA mutations, underlies GBM recurrence, allowing tumor cells to evade targeted therapies. Single-cell lineage tracking reveals that GBM cells dynamically adapt within the TME through complex signaling with astrocytes, microglia, and immune cells, fostering an immunosuppressive microenvironment. Recurrent GBM shows increased T-cell infiltration but is dominated by exhausted CD8+ T cells and regulatory T cells (Tregs), promoting immune evasion. Disrupting these tumor-supportive interactions offers a therapeutic opportunity.
Recurrent GBM shifts toward a mesenchymal phenotype, driving resistance. Targeting mesenchymal transition pathways, such as Activator Protein 1 (AP-1) modulation, may improve therapy. Additionally, reversing CD8+ T-cell exhaustion and Treg-mediated immunosuppression could enhance immunotherapy. Disrupting TME-mediated signaling represents a promising strategy to overcome resistance. This review highlights both cell-intrinsic and cell-extrinsic therapeutic targets and insights from single-cell multiomics for future GBM treatments.
胶质母细胞瘤（GBM）是一种侵袭性原发性脑肿瘤，尽管采用了多模式治疗，但其预后仍然很差。虽然先前的研究集中在肿瘤细胞的演变上，但越来越多的证据表明肿瘤微环境（TME）是治疗耐药性和疾病进展的关键驱动因素。了解GBM与TME的相互作用对于确定新的治疗靶点至关重要。
在PubMed、Embase和Web of Science上进行了全面的文献检索，以查找截至2024年12月的英文研究。对相关的观察性研究、临床试验、荟萃分析和综述进行分析，以评估驱动GBM进展和治疗耐药性的细胞内在和细胞外在机制。
新出现的证据表明，表型可塑性而非DNA突变是GBM复发的基础，使肿瘤细胞能够逃避靶向治疗。单细胞谱系追踪显示，GBM细胞通过与星形胶质细胞、小胶质细胞和免疫细胞的复杂信号在TME中动态适应，从而形成免疫抑制微环境。复发性GBM显示T细胞浸润增加，但以耗竭的CD8+T细胞和调节性T细胞（Tregs）为主，促进了免疫逃逸。破坏这些肿瘤支持性相互作用提供了一个治疗机会。
复发性GBM向间充质表型转变，导致耐药性。靶向间充质转化途径，如激活蛋白1（AP-1）调节，可能会改善治疗效果。此外，逆转CD8+T细胞耗竭和Treg介导的免疫抑制可以增强免疫治疗。破坏TME介导的信号传导是克服耐药性的一个有前景的策略。本综述强调了细胞内在和细胞外在的治疗靶点以及单细胞多组学对未来GBM治疗的启示。
