肿瘤细胞治疗研究
英文原题：Engineering next-generation CAR-T cells for glioblastoma treatment: a review of innovations in receptor design, antigen targeting, and therapeutic persistence.
胶质母细胞瘤（GBM）仍是成人中最具侵袭性的原发性恶性脑肿瘤，其特征为预后差、显著的瘤内异质性以及高度免疫抑制的肿瘤微环境（TME）。
胶质母细胞瘤（GBM）仍是成人中最具侵袭性的原发性恶性脑肿瘤，其特征为预后差、显著的瘤内异质性以及高度免疫抑制的肿瘤微环境（TME）。尽管嵌合抗原受体（CAR）-T 细胞疗法在血液系统恶性肿瘤中已显示出显著疗效，但在 GBM 中的临床反应仍不一致，且很少持久。本综述批判性地评估了受体结构、抗原选择、多抗原靶向、抗 TME 与抗耗竭工程化改造、局部区域递送、替代性 CAR 细胞平台以及计算设计如何应对 GBM 的主要生物学和解剖学屏障。尤其值得关注的是，不仅是临床前活性与有限临床疗效之间的转化差距，还包括靶点特异性、抗原逃逸、安全性、递送途径和 CAR-T 持久性方面的差异。然而，现有证据表明，没有任何单一工程化策略足以克服这些相互关联的屏障。最强的策略很可能是联合多种策略。这些策略应改善抗原覆盖、维持 CAR-T 细胞功能、提高安全性并改善中枢神经系统内的递送。因此，GBM CAR 治疗的未来进展将取决于整合互补的解决方案，而非仅改进单一 CAR 特性。
Glioblastoma (GBM) remains the most aggressive primary malignant brain tumor in adults and is characterized by poor prognosis, profound intratumoral heterogeneity, and a highly immunosuppressive tumor microenvironment (TME). Although chimeric antigen receptor (CAR)-T cell therapy has shown remarkable efficacy in hematologic malignancies, clinical responses in GBM remain inconsistent and rarely durable. This review critically evaluates how receptor architecture, antigen selection, multi-antigen targeting, TME- and exhaustion-resistant engineering, locoregional delivery, alternative CAR-cell platforms and computational design address the major biological and anatomical barriers of GBM. What should be given a particular attention is not only the translational gap between preclinical activity and limited clinical efficacy, but also differences in target specificity, antigen escape, safety, delivery route and CAR-T persistence. However, the available evidence indicates that no single engineering strategy is sufficient to overcome the interconnected barriers. The strongest approach is likely to combine several strategies. These should improve antigen coverage, maintain CAR-T cell function, increase safety and improve delivery within the CNS. Future progress in GBM CAR therapy will therefore depend on combining complementary solutions rather than improving only one CAR feature.
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