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REVIEW

Epigenetic Modulators and Immunotherapy in Malignant Melanoma

Ioannis Anestopoulos1,*, Sotiris Kyriakou1, Maria Deligiorgi2, Dimitrios T. Trafalis2, Sotiris Botaitis3, Rodrigo Franco4,5, Aglaia Pappa6, Mihalis I. Panayiotidis7,*
1 Department of Cancer Genetics, Therapeutics & Ultrastructural Pathology, the Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus
2 Laboratory of Pharmacology, Medical School, National & Kapodistrian University of Athens, Athens, Greece
3 Department of Surgery, School of Medicine, University Hospital, Democritus University of Thrace, Alexandroupolis, Greece
4 School of Veterinary Medicine & Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE, USA
5 Redox Biology Centre, University of Nebraska-Lincoln, Lincoln, NE, USA
6 Department of Molecular Biology & Genetics, Democritus University of Thrace, Alexandroupolis, Greece
7 Department of Comparative Biomedical Sciences, College of Veterinary Medicine, Mississippi State University, Starkville, MS, USA
* Corresponding Author: Ioannis Anestopoulos. Email: email; Mihalis I. Panayiotidis. Email: email

Oncology Research https://doi.org/10.32604/or.2026.072349

Received 25 August 2025; Accepted 09 May 2026; Published online 25 May 2026

Abstract

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.

Keywords

Malignant melanoma; epigenetics; DNA methyltransferase inhibitors; Histone Deacetylase inhibitors; immunotherapy; immune checkpoint inhibitors

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