Epigenetic Modulation of Tumor Immunity

Epigenetic modulation has emerged as a pivotal regulator of tumour immunity, governing both cancer cell immunogenicity and the functional state of immune effectors within the tumour microenvironment. Key mechanisms include DNA methylation, histone modification and chromatin remodelling, which collectively shape the expression of tumour-associated antigens, antigen-presentation machinery and immune-checkpoint molecules. In parallel, epigenetic states of T cells, dendritic cells and macrophages determine lineage commitment, effector differentiation and exhaustion profiles. Dysregulated epigenetic landscapes in cancer can silence immunostimulatory pathways and promote immune escape, while targeted inhibitors of DNA methyltransferases or histone deacetylases can reverse these effects. Therapeutic epigenetic agents have proven capable of unmasking cryptic neoantigens, enhancing MHC expression and skewing cytokine networks to favour T-cell infiltration. By reprogramming both tumour cells and immune populations, epigenetic therapies have shown synergy with immune-checkpoint blockade and adoptive cell transfer, providing a versatile toolkit to overcome resistance in multiple cancer types. The global significance of this approach lies in its potential to convert immunologically ‘cold’ tumours into inflamed, therapy-responsive lesions, thereby broadening the reach of cancer immunotherapy.

Research from Nature Portfolio

Recent studies have demonstrated that combined inhibition of DNA methyltransferases and histone deacetylases induces transcription of endogenous retroviral elements, generating novel polyadenylated transcripts that serve as sources of immunogenic neoantigens. Deep RNA sequencing of treated cancer cell lines revealed thousands of retroviral-derived transcripts, from which a subset of peptides was presented on HLA molecules and shown to activate tumour-specific T cells, both in vitro and in patient samples following hypomethylating therapy. In another line of investigation, a next-generation hypomethylating agent was shown to demethylate and upregulate major histocompatibility complex class I genes in breast cancer models. Treatment with this agent increased tumour cell MHC-I expression in response to interferon-γ, promoted CD8+ T-cell recruitment and enhanced antitumour activity in murine models, with concordant MHC-I upregulation observed in patients receiving treatment. These findings underscore the capacity of epigenetic drugs to unmask antigen presentation pathways and potentiate cytotoxic T-cell responses.

Epigenetic Modulation of Tumor Immunity publication trend

The graph below shows the total number of articles in epigenetic modulation of tumor immunity across all publications each year (not limited to Nature Index journals).

Technical terms

DNA methyltransferase inhibitor (DNMTi): A compound that prevents methyl groups being added to DNA, restoring expression of silenced genes.

Histone deacetylase inhibitor (HDACi): A molecule that blocks removal of acetyl groups from histone proteins, promoting a more open chromatin state and gene activation.

Endogenous retroviral element (ERV): A viral sequence embedded in the genome whose transcription can yield novel antigenic peptides when de-repressed.

Major histocompatibility complex class I (MHC-I): A cell surface protein complex that presents intracellular peptides to CD8+ T cells.

Neoantigen: A tumour-specific peptide, often arising from mutations or de-repressed genomic regions, recognised as non-self by the immune system.

References

1. DNMT and HDAC inhibition induces immunogenic neoantigens from human endogenous retroviral element-derived transcripts. Nature Communications (2023).
2. DNA methyltransferase inhibition upregulates MHC-I to potentiate cytotoxic T lymphocyte responses in breast cancer. Nature Communications (2018).
3. Epigenetic regulation in the tumor microenvironment: molecular mechanisms and therapeutic targets. Signal Transduction and Targeted Therapy (2023).
4. Nano‐Regulator Inhibits Tumor Immune Escape via the “Two‐Way Regulation” Epigenetic Therapy Strategy. Advanced Science (2023).
5. Epigenetic modulation of antitumor immunity for improved cancer immunotherapy. Molecular Cancer (2021).