BUFFALO, NY – September 9, 2026 – A new review was published in Volume 17 of Oncotarget on September 8, 2026, titled “ Re-expression of MHC-I to treat CNS cancers .”
The review examines emerging strategies to restore major histocompatibility complex class I (MHC-I) expression in cancers of the central nervous system (CNS), with the goal of making these tumors more visible and vulnerable to immune attack.
The review was authored by Arseniy E. Yuzhalin from the Sirius University of Science and Technology in Sochi, Russia . Yuzhalin is also the corresponding author.
Malignant central nervous system (CNS) tumors such as glioblastoma and brain metastases are often immunologically “cold,” with limited T-cell infiltration and poor responses to immune checkpoint therapy. One important mechanism of immune escape is the reduction or loss of major histocompatibility complex class I (MHC-I), which normally displays tumor-associated antigens to cytotoxic CD8+ T cells. When MHC-I expression falls, cancer cells become less visible to immune surveillance.
The review examines several strategies for restoring MHC-I expression. Epigenetic therapies, including histone deacetylase and DNA methyltransferase inhibitors, could potentially reverse epigenetic silencing of MHC-I genes, although blood-brain barrier penetration remains a major limitation in CNS cancers. A more direct approach could use adeno-associated virus (AAV) vectors to deliver patient-specific HLA-A, HLA-B, or HLA-C genes or transcription factors such as NLRC5 that promote MHC-I expression. However, efficient tumor targeting, gene delivery, and control of the immunosuppressive tumor microenvironment remain unresolved challenges.
The review also highlights PCSK9 inhibition as a clinically relevant strategy. PCSK9 can promote MHC-I degradation, and a recent surgical-window trial tested the cholesterol-lowering drug evolocumab in patients with newly diagnosed or recurrent glioma. A single preoperative dose showed measurable blood-brain barrier penetration, and tumors with higher drug concentrations displayed increased surface MHC-I expression, greater CD8+ T-cell infiltration, and enhanced cytotoxic activity. These findings provide proof-of-mechanism, although drug delivery into the brain remains a limiting factor.
Another approach is to modify the tumor microenvironment. Interferons can increase MHC-I and antigen-processing machinery, while disrupting communication between cancer cells and surrounding brain cells may also restore immune visibility. In mouse models of brain metastasis, inhibition of Cdk5 with roscovitine restored MHC-I expression and improved CD8+ T-cell responses, particularly when combined with immune checkpoint blockade. This strategy, however, remains preclinical.
MHC-I restoration may also complement cellular immunotherapies. CAR-T cells recognize tumor-surface antigens independently of MHC-I, but antigen-negative tumor clones can emerge during treatment. Restoring MHC-I could potentially allow endogenous CD8+ T cells to recognize some of these escape populations. CAR-NK therapy may provide another complementary route, with carefully sequenced approaches potentially combining early NK-cell-mediated tumor killing with longer-term CD8+ T-cell surveillance.
Importantly, simply increasing MHC-I surface expression may not be enough. CNS tumors can also have defects in antigen-processing machinery, including TAP proteins, peptide-loading components, NLRC5, and beta-2 microglobulin. Their relatively low mutational burden can further restrict the number of neoantigens available for immune recognition. The review therefore emphasizes that successful MHC-I restoration may require simultaneous improvement of antigen processing and peptide presentation.
Radiotherapy could provide another opportunity for combination treatment. Radiation-induced DNA damage can activate the cGAS-STING pathway, stimulating type I interferon signaling and increasing MHC-I expression. However, this response can be temporary, and glioblastoma cells may suppress STING signaling. Combining radiotherapy with STING agonists, epigenetic therapies, or other immune-modulating strategies may therefore help sustain tumor immunogenicity, although these approaches remain largely experimental.
“ Undoubtedly, re-expression of MHC-I for the treatment of CNS cancers will likely achieve success only as part of multimodal regimens combining surgical resection, temozolomide and focal or whole brain radiotherapy .”
Significant barriers remain. The blood-brain barrier restricts delivery of many therapeutic agents, while CNS tumors show substantial genetic and molecular heterogeneity. Some tumors also harbor irreversible genetic loss of HLA or beta-2 microglobulin that cannot simply be reversed pharmacologically. In addition, restoring MHC-I alone cannot overcome defective antigen processing or a limited neoantigen repertoire.
Overall, the review presents MHC-I re-expression as a promising strategy for making CNS tumors more visible to the immune system, but one that will likely require combination therapy rather than a stand-alone approach. Integrating MHC-I restoration with chemoradiotherapy, immune checkpoint blockade, gene therapy, cellular immunotherapy, and other immune-modulating strategies could potentially improve antitumor immune responses. Further preclinical and clinical studies are needed to determine which combinations are safe, feasible, and effective for patients with CNS cancers.
DOI: https://doi.org/10.18632/oncotarget.28917
Correspondence to: Arseniy E. Yuzhalin – yuzhalin.ae@talantiuspeh.ru
Abstract video: https://www.youtube.com/watch?v=NDvQ7QS3DFg
Keywords : brain tumor, CNS cancer, glioblastoma, brain metastasis, MHC-I
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Oncotarget
Literature review
Not applicable
Re-expression of MHC-I to treat CNS cancers
8-Sep-2026
Author has no conflicts of interest to declare.