Targeting the Epigenetic-Immune Axis in Acute Myeloid Leukemia: Current Advances and Future Directions

Acute myeloid leukemia (AML) exemplifies how malignant transformation can be driven by both epigenetic deregulation and genetic mutation. Aberrant DNA methylation, histone modifications, and chromatin remodelling cooperate to block myeloid differentiation, sustain leukemic self-renewal, and promote immune evasion. This review examines the molecular mechanisms underlying epigenetic dysregulation in AML and highlights recent advances in epigenetic and immune-based therapeutic strategies.

Recent studies have identified multiple druggable epigenetic regulators, including DNA methyltransferases, TET dioxygenases, histone methyltransferases and demethylases, and histone acetyltransferases and deacetylases. These discoveries have led to the development of hypomethylating agents, mutant IDH1/2 inhibitors, menin-MLL and DOT1L antagonists, EZH2 and LSD1 inhibitors, and class-specific HDAC inhibitors, several of which are approved or undergoing advanced clinical evaluation. Beyond reprogramming leukemic transcriptional networks, epigenetic therapies also remodel the immune microenvironment by influencing antigen presentation and immune checkpoint pathways, providing a rationale for combination approaches with antibody-drug conjugates, bispecific T-cell or NK-cell engagers, aptamer-directed therapeutics, vaccines, and CAR-T/NK cell therapies targeting CD33, CD123, FLT3, CLL-1, and other AML-associated antigens. The integration of epigenetic modulation with immunotherapeutic and precision medicine approaches represents a promising strategy to overcome disease heterogeneity and therapeutic resistance in AML. By bridging mechanistic insights with translational advances, clinical trial evidence, and emerging patent landscapes, this review highlights epigenetic dysregulation as both a fundamental driver of leukemogenesis and a clinically actionable therapeutic interface that may enable more rational treatment sequencing and personalized AML management.