Glioblastoma (GBM) is an aggressive primary brain tumor depicted by a cold tumor microenvironment, low immunogenicity, and limited effective therapeutic interventions. Its location in the brain, a highly immune-selective organ, acts as a barrier, limiting immune access and promoting GBM dissemination, despite therapeutic interventions. Currently, chemotherapy and radiation combined with surgical resection are the standard of care for GBM treatment. Although immune checkpoint blockade has revolutionized the treatment of solid tumors, its observed success in extracranial tumors has not translated into a significant survival benefit for GBM patients. To develop effective immunotherapies for GBM, it is vital to tailor treatments to overcome the numerous immunosuppressive barriers that inhibit T cell responses to these tumors. In this review, we address the unique physical and immunological barriers that make GBM challenging to treat. Additionally, we explore potential therapeutic mechanisms, studied in central nervous system (CNS) and non-CNS cancers, that may overcome these barriers. Furthermore, we examine current and promising immunotherapy clinical trials and immunotherapeutic interventions for GBM. By highlighting the array of challenges T cell-based therapies face in GBM, we hope this review can guide investigators as they develop future immunotherapies for this highly aggressive malignancy.
胶质母细胞瘤（GBM）是一种侵袭性原发性脑肿瘤，其特征表现为肿瘤微环境呈“冷”状态、免疫原性低且有效治疗手段有限。尽管存在多种治疗干预措施，但GBM位于具有高度免疫选择性的脑组织内，这一特殊位置形成了天然屏障，既限制了免疫细胞的浸润，又促进了肿瘤的扩散。目前，手术切除联合放化疗是GBM的标准治疗方案。虽然免疫检查点阻断疗法已彻底改变了实体瘤的治疗格局，但其在颅外肿瘤中取得的显著成效并未转化为GBM患者的生存获益。要开发针对GBM的有效免疫疗法，关键在于设计能够突破多重免疫抑制屏障的治疗策略，这些屏障会抑制T细胞对肿瘤的免疫应答。本综述系统阐述了导致GBM难以治疗的独特物理屏障与免疫屏障，同时探讨了在中枢神经系统（CNS）及非CNS癌症研究中发现的、可能突破这些屏障的潜在治疗机制。此外，我们还分析了当前及前景广阔的GBM免疫治疗临床试验与干预策略。通过系统梳理基于T细胞的疗法在GBM治疗中面临的多重挑战，本综述旨在为研究者开发针对这种高度侵袭性恶性肿瘤的新型免疫疗法提供理论指导。
Barriers to T Cell Functionality in the Glioblastoma Microenvironment
肿瘤(癌症)患者之家