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Immunotherapy Resistance in Glioblastoma
Open accessAbstract
Glioblastoma is the most common malignant primary brain tumor in adults. Despite treatment consisting of surgical resection followed by radiotherapy and adjuvant chemotherapy, survival remains poor at a rate of 26.5% at 2 years. Recent successes in using immunotherapies to treat a number of solid and hematologic cancers have led to a growing interest in harnessing the immune system to target glioblastoma. Several studies have examined the efficacy of various immunotherapies, including checkpoint inhibitors, vaccines, adoptive transfer of lymphocytes, and oncolytic virotherapy in both pre-clinical and clinical settings. However, these therapies have yielded mixed results at best when applied to glioblastoma. While the initial failures of immunotherapy were thought to reflect the immunoprivileged environment of the brain, more recent studies have revealed immune escape mechanisms created by the tumor itself and adaptive resistance acquired in response to therapy. Several of these resistance mechanisms hijack key signaling pathways within the immune system to create a protumoral microenvironment. In this review, we discuss immunotherapies that have been trialed in glioblastoma, mechanisms of tumor resistance, and strategies to sensitize these tumors to immunotherapies. Insights gained from the studies summarized here may help pave the way for novel therapies to overcome barriers that have thus far limited the success of immunotherapy in glioblastoma.
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“GBM immunoresistance may also be acquired in response to therapy, through changes in checkpoint expression, epigenetic changes, and loss of tumour antigen expression [10].”
From Preclinical development of an mRNA-based multiepitope immunotherapeutic for glioblastoma (2025) · cites this paper as [10]
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“Tumour cell heterogeneity and an immunosuppressive microenvironment contribute to primary GBM immunoresistance, which dampens anti-tumour responses by macrophages and T cells [7, 10].”
From Preclinical development of an mRNA-based multiepitope immunotherapeutic for glioblastoma (2025) · cites this paper as [10]
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Metadata
- Authors
- Wang, E. J., Chen, J.-S., Jain, S., Morshed, R. A., Haddad, A. F., Gill, S., Beniwal, A. S., & Aghi, M. K.
- Affiliations
- Brown University (US)
- University of California, San Francisco (US)
- Corresponding author
- Aghi, Manish K.
- ORCID
- Venue
- Frontiers in Genetics
- Publisher
- Frontiers Media SA
- Published
- 2021-12-17
- Volume
- 12
- Pages
- 750675-750675
- ISSN
- 1664-8021 (ISSN-L)
- PMC
- PMC8718605
- OpenAlex
- W4200562336
- Cited by
- 34
- References
- 269
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 8 · 2023: 12 · 2022: 2
- FWCI
- 0.78
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Genetics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- National Cancer Institute (R01CA227136)
- National Institute of Neurological Disorders and Stroke (R01NS079697)
- Topics
- Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- glioblastoma, immunotherapy resistance, immune checkpoint inhibitors, cancer vaccines, adoptive immunotherapy, oncolytic virotherapy, tumor immune evasion, tumor microenvironment, immune privilege, adaptive resistance, radiosensitization
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