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  • Epigenetic Modulation of Immune Checkpoints and Tumor Immune Signaling

  • Elahe Mahdiuni,1,* Mahdi Kazemzad,2
    1. Maraghe University
    2. Shahid Ashrafi University of Isfahani


  • Introduction: Cancer remains one of the leading causes of mortality worldwide, and immune evasion is recognized as a fundamental hallmark of tumor progression. Central to this immune escape is the dysregulation of immune checkpoint pathways, such as PD-1/PD-L1, CTLA-4, LAG-3, and TIM-3, which normally function to maintain immune tolerance and prevent autoimmunity. In the tumor microenvironment (TME), malignant cells exploit these inhibitory pathways to suppress T-cell activation and avoid immune destruction. In parallel, growing evidence highlights the crucial role of epigenetic modifications—heritable but reversible changes in gene expression without alterations in the DNA sequence in shaping both cancer cell behavior and antitumor immunity. DNA methylation, histone modifications, chromatin remodeling, and noncoding RNAs can dictate the expression of immune checkpoints, antigen-presentation machinery, cytokines, and chemokines, thereby controlling the dynamic interactions between tumors and immune cells. Importantly, epigenetic mechanisms not only regulate the expression of checkpoint ligands and receptors but also influence the differentiation and function of immune cells themselves. For instance, methylation patterns in T cells and macrophages determine their effector versus suppressive phenotypes, while noncoding RNAs modulate immune exhaustion and regulatory pathways. The integration of epigenetics into immuno-oncology has led to an emerging paradigm: epigenetic therapy can “reprogram” the TME, enhance immunogenicity, and synergize with immune checkpoint inhibitors (ICIs). Indeed, early-phase clinical trials suggest that combining DNA methyltransferase (DNMT) inhibitors or histone deacetylase (HDAC) inhibitors with PD1/PD-L1 blockade can overcome resistance in solid and hematologic malignancies.
  • Methods: We performed a comprehensive literature synthesis of primary research and clinical studies (PubMed, major journals) through 2025, focusing on mechanistic work and translational/clinical evidence for epigenetic regulation of immune checkpoints and combinatorial therapies.
  • Results: Evidence indicates that DNA methylation and histone-mark changes at promoters/enhancers control checkpoint ligand/receptor expression and antigen-presentation genes; chromatin remodeling affects enhancer accessibility of immune-related loci. Noncoding RNAs (miRNAs, lncRNAs , circRNAs) and m⁶A epitranscriptomic modifications modulate stability/translation of immune transcripts and immune-cell phenotypes. Preclinical and emerging clinical data show that epigenetic agents (DNMT inhibitors, HDAC inhibitors, EZH2 and other chromatin-modifier inhibitors) can reprogram the TME, increase tumor immunogenicity and T-cell infiltration, and sensitize tumors to PD-1/PD-L1 blockade in resistant settings.
  • Conclusion: Targeting epigenetic regulators offers a promising strategy to overcome immune-evasion and improve checkpoint-inhibitor responses. Key challenges remain—tumor and TME heterogeneity, optimal sequencing/dosing, predictive biomarkers, and safety of combinations. We propose a framework for biomarker-driven combinatorial trials and highlight priority mechanistic gaps for future research.
  • Keywords: epigenetics; immune checkpoints; tumor microenvironment; PD-1/PD-L1; DNMT inhibitors

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