Li Zhipeng, Yang Fan, Lu Siyuan, Wu Xinhao, Li Shenglong, Wang Minghao
Department of Neurosurgery, First Affiliated Hospital of China Medical University, Shenyang, China.
Department of Cardiology of the Fourth Affiliated Hospital of China Medical University, Shenyang, China.
Cancer Lett. 2025 Jul 15;631:217928. doi: 10.1016/j.canlet.2025.217928.
Glioma, a category of the most lethal primary brain tumors, remains incurable despite multimodal therapy combining maximal resection, radiation, and temozolomide. These interventions invariably fail due to residual invasive cells, molecular heterogeneity, and an immunosuppressive tumor microenvironment (TME) reinforced by myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). The blood-brain barrier (BBB) further limits therapeutic access, while antigen escape and T-cell exclusion mechanisms drive relapse. Chimeric antigen receptor (CAR) T-cell therapy, transformative in relapsed B-cell malignancies with sustained remission rates, faces formidable yet surmountable barriers in solid tumors. Recent advances in CAR-T trials targeting glioma-associated antigens demonstrate partial intracranial activity, albeit with transient efficacy, underscoring the need for neuroimmunology-informed engineering. This review critically evaluates CAR-T strategies countering glioma-specific resistance: bispecific antigen targeting combats tumor plasticity, cytokine-armored designs neutralize immunosuppression, and innovative delivery routes enhance CNS bioavailability. Early clinical outcomes reveal critical divergence points from hematologic success, including antigen loss due to glioma's evolutionary capacity and T-cell exhaustion within hypoxic niches. Emerging solutions integrate CRISPR-edited allogeneic platforms with combinatorial immunomodulation (e.g., myeloid-targeting) and delivery innovations to address these barriers. We further dissect translational priorities including neurotoxicity mitigation and scalable manufacturing for infiltrative glioma phenotypes. By converging advances in immune-engineering, TME remodeling, and biomarker-driven trial designs, this work proposes a roadmap to achieve durable CAR-T efficacy in GBM. The synthesis bridges mechanistic insights into glioma-immune interactions with clinical translation strategies, aiming to transcend current limitations of transient cytoreduction and establish CAR-T therapy as a cornerstone of neuro-oncologic practice.
胶质瘤是一类最致命的原发性脑肿瘤，尽管采用了最大程度切除、放疗和替莫唑胺联合的多模式治疗，仍无法治愈。由于残留的侵袭性细胞、分子异质性以及由髓源性抑制细胞（MDSC）和调节性T细胞（Treg）强化的免疫抑制肿瘤微环境（TME），这些干预措施总是失败。血脑屏障（BBB）进一步限制了治疗的可达性，而抗原逃逸和T细胞排斥机制则导致复发。嵌合抗原受体（CAR）T细胞疗法在复发性B细胞恶性肿瘤中具有变革性，缓解率持续，但在实体瘤中面临着巨大但可克服的障碍。针对胶质瘤相关抗原的CAR-T试验的最新进展显示出部分颅内活性，尽管疗效短暂，这凸显了基于神经免疫学的工程设计的必要性。本综述批判性地评估了对抗胶质瘤特异性耐药性的CAR-T策略：双特异性抗原靶向可对抗肿瘤可塑性，细胞因子武装设计可中和免疫抑制，创新的递送途径可提高中枢神经系统的生物利用度。早期临床结果揭示了与血液学成功的关键分歧点，包括由于胶质瘤的进化能力导致的抗原丢失以及缺氧微环境中的T细胞耗竭。新兴的解决方案将CRISPR编辑的同种异体平台与组合免疫调节（如靶向髓系细胞）和递送创新相结合，以克服这些障碍。我们进一步剖析了转化研究的重点，包括减轻神经毒性和为浸润性胶质瘤表型进行可扩展的制造。通过整合免疫工程、TME重塑和生物标志物驱动的试验设计方面的进展，这项工作提出了一条在胶质母细胞瘤中实现持久CAR-T疗效的路线图。本综述将对胶质瘤-免疫相互作用的机制性见解与临床转化策略相结合，旨在超越目前短暂细胞减灭的局限性，并将CAR-T疗法确立为神经肿瘤学实践的基石。
