Epigenetic Modulators and Immunotherapy in Malignant Melanoma

Despite the use of targeted and/or immune-based therapeutic approaches, mortality rates among melanoma patients are high, mainly due to drug-induced resistance mechanisms. In parallel, alterations of epigenetic mechanisms (e.g., deregulated patterns of DNA methylation, aberrant histone modifications and abnormal expression levels of non-coding RNAs [ncRNAs]) have been associated not only with the pathophysiology of melanoma but also with the resistance against various immunotherapeutic drugs. In this review article, we discuss the involvement of different types of epigenetic mechanisms in melanoma progression. In addition, we report on melanoma’s immune environment and immunosuppressive mechanisms while we highlight the role of immune checkpoint inhibitors (ICIs) as an anti-melanoma therapeutic approach. Moreover, we describe the underlying mechanism(s) by which deregulated epigenetic patterns promote drug resistance against ICIs and how epigenetic drugs (utilized either alone or in combination with various ICIs) can reverse immune resistance. Furthermore, we discuss the major limitations and future directions towards clinical translation of epigenetic drugs, mainly in combination with ICIs. Finally, we state the potential use of emerging technologies (e.g., single-cell transcriptomics and spatial transcriptomics), along with epigenetic priming for improvement of clinical implementation and therapeutic outcomes in melanoma management.