Epigenetic dysregulation in mycosis fungoides and sézary syndrome

Cutaneous T-cell lymphomas (CTCL), including mycosis fungoides (MF) and Sézary syndrome (SS), remain challenging to diagnose at early stages and to manage durably. Although staging and classification have improved, early MF can mimic benign inflammatory dermatoses, and advanced disease frequently develops resistance to standard therapies, including histone deacetylase (HDAC) inhibitors. Here, we summarize how aberrant DNA methylation and histone modifications contribute to CTCL pathogenesis, promote a permissive tumor microenvironment, and enable immune escape, as well as emerging epigenetic biomarkers, such as microRNA signatures and promoter hypermethylation, that may improve diagnostic accuracy and patient stratification. Finally, we discuss resistance mechanisms linked to epigenetic plasticity and intratumoral heterogeneity and highlight future strategies combining rational drug regimens with longitudinal single-cell profiling to improve the durability of response.