Cell-Intrinsic and Cell-Extrinsic Therapeutic Targets in Glioblastoma: Overcoming Resistance Through Tumor Microenvironment Modulation and Precision Medicine

IF 2.1 4区医学 Q3 CLINICAL NEUROLOGY

World neurosurgery Pub Date : 2025-07-01 DOI:10.1016/j.wneu.2025.124142

Siddharth Shah , Brandon Lucke-Wold

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引用次数: 0

Abstract

Background

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.

Methods

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.

Results

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, promoting immune evasion. Disrupting these tumor-supportive interactions offers a therapeutic opportunity.

Conclusions

Recurrent GBM shifts toward a mesenchymal phenotype, driving resistance. Targeting mesenchymal transition pathways, such as activator protein 1 modulation, may improve therapy. Additionally, reversing CD8+ T-cell exhaustion and regulatory T cell-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.

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胶质母细胞瘤的细胞内源性和细胞外源性治疗靶点：通过肿瘤微环境调节和精准医学克服耐药性。

背景：胶质母细胞瘤（GBM）是一种侵袭性原发性脑肿瘤，尽管采用多种治疗方式，但预后较差。虽然之前的研究主要集中在肿瘤细胞的进化上，但越来越多的证据强调肿瘤微环境（tumor microenvironment， TME）是治疗耐药性和疾病进展的关键驱动因素。了解GBM-TME相互作用对于确定新的治疗靶点至关重要。方法：在PubMed、Embase和Web of Science中检索截至2024年12月的英语研究文献。相关的观察性研究、临床试验、荟萃分析和综述进行了分析，以评估驱动GBM进展和治疗耐药的细胞内在和细胞外在机制。结果：新出现的证据表明，表型可塑性，而不是DNA突变，是GBM复发的基础，使肿瘤细胞逃避靶向治疗。单细胞谱系追踪显示，GBM细胞通过星形胶质细胞、小胶质细胞和免疫细胞的复杂信号传导，在TME内动态适应，形成免疫抑制微环境。复发性GBM表现为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，促进免疫逃避。破坏这些支持肿瘤的相互作用提供了一个治疗的机会。结论：复发性GBM向间质表型转移，驱动耐药性。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。此外，逆转CD8+ t细胞衰竭和treg介导的免疫抑制可以增强免疫治疗。破坏tme介导的信号是克服耐药性的一种有希望的策略。这篇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治疗的见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

World neurosurgery CLINICAL NEUROLOGY-SURGERY

CiteScore

3.90

自引率

15.00%

发文量

1765

审稿时长

47 days

期刊介绍： World Neurosurgery has an open access mirror journal World Neurosurgery: X, sharing the same aims and scope, editorial team, submission system and rigorous peer review. The journal''s mission is to: -To provide a first-class international forum and a 2-way conduit for dialogue that is relevant to neurosurgeons and providers who care for neurosurgery patients. The categories of the exchanged information include clinical and basic science, as well as global information that provide social, political, educational, economic, cultural or societal insights and knowledge that are of significance and relevance to worldwide neurosurgery patient care. -To act as a primary intellectual catalyst for the stimulation of creativity, the creation of new knowledge, and the enhancement of quality neurosurgical care worldwide. -To provide a forum for communication that enriches the lives of all neurosurgeons and their colleagues; and, in so doing, enriches the lives of their patients. Topics to be addressed in World Neurosurgery include: EDUCATION, ECONOMICS, RESEARCH, POLITICS, HISTORY, CULTURE, CLINICAL SCIENCE, LABORATORY SCIENCE, TECHNOLOGY, OPERATIVE TECHNIQUES, CLINICAL IMAGES, VIDEOS