Unraveling epigenetic drivers of immune evasion in gliomas: mechanisms and therapeutic implications

Abstract

Gliomas are the most common primary malignant tumors of the central nervous system (CNS), and despite progress in molecular diagnostics and targeted therapies, their prognosis remains poor. In recent years, immunotherapy has emerged as a promising treatment modality in cancer therapy. However, the inevitable immune evasion by tumor cells is a key barrier affecting therapeutic efficacy. Epigenetic regulation, such as DNA methylation, histone modification, and non-coding RNA expression, plays a crucial role in the occurrence, development, and immune evasion of gliomas. These modifications can dynamically regulate gene expression, leading to the silencing of tumor-associated antigens, dysregulation of pro-inflammatory cytokines, and dynamic modulation of immune checkpoints (such as PD-L1). This review systematically elucidates the key mechanisms by which epigenetic regulation promotes immune evasion in gliomas and details three interconnected mechanisms: 1) epigenetic silencing of tumor-associated antigens and antigen-presenting machinery; 2) dysregulation of pro-inflammatory cytokine secretion; and 3) dynamic modulation of PD-L1 expression through chromatin remodeling. We emphasize the potential of combining epigenetic therapies with immunotherapies to enhance anti-tumor immune responses and overcome treatment resistance in gliomas. Future research should focus on developing biomarker-driven epigenetic immunotherapies and exploring the complex interplay between epigenetic modifications, glioma cells, and the tumor immune microenvironment to improve patient outcomes.

Keywords: CAR-T cell therapy; epigenetic regulations; gliomas; immune evasion; non-coding RNA.

Figure 1

In IDH wild-type glioma cells (left), isocitrate is converted into α-ketoglutarate and NADPH using NADP⁺ under the action of the IDH2 enzyme dimer. α-ketoglutarate then enters the nucleus and participates in α- ketoglutarate-dependent enzymatic reactions, promoting DNA and histone demethylation. In IDH mutant glioma cells (right), the mutated IDH enzyme catalyzes the conversion of isocitrate to 2-hydroxyglutarate (2-HG), leading to intracellular accumulation of this metabolite. By inhibiting the function of α-ketoglutarate-dependent enzymes, 2-HG obstructs DNA and histone demethylation processes, thereby impacting gene expression modulation.

Figure 2

In GBM cells, overexpression of NamiRNA-141 activates enhancer activity, positively regulates PHB2 to induce nucleolar stress, inhibit ribosome biogenesis, and enhance the chemosensitivity of GBM to temozolomide. H3K27ac is an epigenetic marker of active enhancers.

Figure 3

Differences in super-enhancers and related mechanisms of action between normal brain tissues and glioma samples. In normal brain tissues, the cis-acting super-enhancer landscape is relatively stable. In contrast, super-enhancer reprogramming occurs in glioma samples, thereby activating oncogenes such as ELOVL2 and KLHDC8A. The super-enhancer region involves interactions among various proteins, including CBP30, EP300, BRD4, Med, CDK7, and Pol II. The acetylation sites (AC) on these proteins are involved in the regulatory process. The small-molecule inhibitors JQ1 and THZ1 act on BRD4 and CDK7 respectively. By interfering with the super-enhancer machinery, they intervene in the expression of glioma-related genes.

Figure 4

Conceptual illustration of the crosstalk between glioma cell populations and naive T lymphocytes. Glioma-derived cells release primary cytokines (including IL-6, IL-4, IL-12), triggering the activation of cognate transcription factors (such as STAT3, GATA3, T-bet) in naive T cells. These activated transcription factors guide naive T cells to differentiate into different lymphocyte subsets (including Tfh, TH2, TH1, etc.). Subsequently, these subsets produce 2nd-order cytokines (like IL-21, IL-5, IF-γ), which play important roles in the TME and immune regulation.

Figure 5

Schematic illustration of the mechanisms underlying glioma immune escape and enhanced CAR-T cell infiltration. On the left, in glioma cells, the expression of PD-1 and TIM-3, along with the release of cytokines such as CXCL, TNF, and IFNγ, contributes to immune escape. On the right, the introduction of DNMT in CAR-T cells modulates the cellular environment, reducing immune-suppressive factors and enhancing the infiltration ability of CAR-T cells into glioma tissues.