Understanding the epigenetic regulation of tumours and their microenvironments: opportunities and problems for epigenetic therapy.

The tumour microenvironment plays an instrumental role in cancer development, progression and treatment response/resistance. Accumulating evidence is underscoring the fundamental importance of epigenetic regulation in tumour immune evasion. Following many pioneering discoveries demonstrating malignant transformation through epigenetic anomalies ('epimutations'), there is also a growing emphasis on elucidating aberrant epigenetic mechanisms that reprogramme the milieu of tumour-associated immune and stromal cells towards an immunosuppressive state. Pharmacological inhibition of DNA methylation and histone modifications can augment the efficiency of immune checkpoint blockage, and unleash anti-tumour T-cell responses. However, these non-specific agents also represent a 'double-edged sword', as they can also reactivate gene transcription of checkpoint molecules, interrupting immune surveillance programmes. By understanding the impact of epigenetic control on the tumour microenvironment, rational combinatorial epigenetic and checkpoint blockage therapies have the potential to harness the immune system for the treatment of cancer.