Targeting the Epigenetic–Immune Axes in Hematologic Malignancies

Despite significant advances in treatment for several hematologic malignancies, treatment resistance and relapse remain major challenges. Immune escape is recognized as a key mechanism that can lead to tumor evasion and treatment resistance in blood cancers. Among the various drivers of immune evasion, epigenetic dysregulation is a recurrent and central feature in these malignancies. Although epigenetic targeting therapies have shown benefit in blood cancers, relapse still occurs, indicating the need for improved therapies. This review focuses on epigenetic mechanisms causing immune evasion in blood cancers and discusses emerging therapies that focus on combining epigenetic modulators with immunotherapies to improve anti-tumor immunity. We focus on how epigenetic mechanisms, including DNA methylation, histone modification and chromatin remodeling, influence tumor cells or immune cell subsets including T cells, NK cells and macrophages to promote tumor growth. We then discuss immunomodulatory effects of epigenetic therapies including DNA methyltransferase inhibitors and histone deacetylase inhibitors and how they can restore immune cell function and limit tumor growth and progression. Finally, we highlight the potential of combining epigenetics with different immunotherapies including adoptive cell therapy and immune checkpoint blockade, while discussing their current limitations and suggesting ways to overcome this therapy resistance. A deeper understanding of the immune–epigenetic axis in blood cancers may facilitate the development of effective therapies that will benefit patients with hematologic malignancies.