Epigenetics in disease prevention, cure, and treatment: Role of histone modifiers in immune modulation

Epigenetic regulation has surfaced as a critical determinant of cancer progression, immune evasion, and treatment outcomes. Unlike permanent genomic alterations, epigenetic changes such as histone acetylation, methylation, DNA methylation, and chromatin remodeling are reversible, offering opportunities to influence tumor behavior and overcome therapeutic resistance. Histone modifiers such as histone deacetylases (HDACs), histone methyltransferases, and demethylases affect chromatin accessibility, consequently shaping antigen presentation, cytokine pathways, immune cell infiltration, and tumor–immune dynamics. Abnormal histone modifications attenuate tumor immunogenicity, change macrophage polarization, drive T-cell exhaustion, and promote immune escape. Epigenetic agents such as HDAC inhibitors, DNA methyltransferase inhibitors, enhancer of zeste homolog 2 inhibitors, bromodomain and extraterminal inhibitors, and lysine-specific demethylase-1 inhibitors can reinstate antigen-processing systems, boost T-cell cytotoxicity, and remodel the tumor microenvironment to assist antitumor immunity. When paired with immune checkpoint therapies, Chimeric Antigen Receptor T (CAR-T) cells, or cancer vaccines, these drugs demonstrate synergistic benefits in preclinical and early clinical trials, enhancing tumor suppression and overcoming therapeutic resistance. Precision oncology effectively utilizes epigenetic indicators such as histone Post-Translational Modification (PTM) profiles, DNA methylation patterns, and liquid biopsy-based circulating epigenetic markers to classify patients and guide personalized therapeutic strategies. Upcoming methods such as single-cell multi-omics, artificial intelligence-driven predictive systems, and nanoparticle-based targeted delivery further enhance epigenetic-immune profiling and improve therapeutic accuracy. Despite limitations involving tumor variability, toxicity, and evolving resistance, incorporation of histone modifiers into immunotherapeutic strategies is transforming cancer therapy. Epigenetic remodeling provides a compelling approach to transform immunologically “cold” tumors into “hot” responsive ones, enabling individualized immunoepigenetic strategies with enhanced efficacy and minimal therapeutic resistance.