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Overcoming immunotherapy resistance in glioblastoma: challenges and emerging strategies
Maowu Fu1, Bing Xue2, Xiuming Miao3
1Department of Neurosurgery, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China.
Abstract:
Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults, characterized by rapid proliferation, extensive infiltration, and significant intratumoral heterogeneity. Despite advancements in conventional treatments, including surgery, radiotherapy, and chemotherapy, the prognosis for GBM patients remains poor, with a median survival of approximately 15 months. Immunotherapy has emerged as a promising alternative; however, the unique biological and immunological features, including its immunosuppressive tumor microenvironment (TME) and low mutational burden, render it resistant to many immunotherapeutic strategies. This review explores the key challenges in GBM immunotherapy, focusing on immune evasion mechanisms, the blood-brain barrier (BBB), and the TME. Immune checkpoint inhibitors and CAR-T cells have shown promise in preclinical models but have limited clinical success due to antigen heterogeneity, immune cell exhaustion, and impaired trafficking across the BBB. Emerging strategies, including dual-targeting CAR-T cells, engineered immune cells secreting therapeutic molecules, and advanced delivery systems to overcome the BBB, show potential for enhancing treatment efficacy. Addressing these challenges is crucial for improving GBM immunotherapy outcomes.
Insights
Glioblastoma immunotherapy faces challenges like immune evasion and the blood-brain barrier. Novel strategies like advanced CAR-T cells show promise for improving glioblastoma treatment outcomes.
Area of Science:
- Neuro-oncology
- Immunology
- Cancer Biology
Background:
- Glioblastoma (GBM) is an aggressive primary brain tumor with poor prognosis despite standard treatments.
- Current immunotherapies face resistance due to GBM's immunosuppressive tumor microenvironment (TME) and low mutational burden.
Purpose of the Study:
- To review the challenges and emerging strategies for glioblastoma immunotherapy.
- To highlight immune evasion, blood-brain barrier (BBB) penetration, and TME as key obstacles.
Main Methods:
- Literature review focusing on glioblastoma immunotherapy.
- Analysis of immune evasion mechanisms, BBB limitations, and TME characteristics.
- Evaluation of current and novel immunotherapeutic approaches, including CAR-T cells.
Main Results:
- Preclinical successes of immune checkpoint inhibitors and CAR-T cells are limited in clinical settings.
- Antigen heterogeneity, immune cell exhaustion, and BBB impede effective immunotherapy.
- Emerging strategies like dual-targeting CAR-T cells and advanced delivery systems show potential.
Conclusions:
- Overcoming glioblastoma's unique immunological challenges is critical for therapeutic advancement.
- Novel approaches are needed to enhance immune cell trafficking and efficacy across the BBB.
- Further research into engineered immune cells and delivery systems may improve patient outcomes.
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