Targeting epigenetic reprogramming in DLBCL and its interaction with the tumor microenvironment for novel therapeutic approaches.

Diffuse large B-cell lymphoma (DLBCL), the most common aggressive form of non-Hodgkin lymphoma, despite significant advancements in therapy, a substantial proportion of patients will relapse or exhibit refractory disease. DLBCL exhibits complex interactions between tumor cells and their microenvironment, significantly influenced by epigenetic dysregulation. Recent advances in genomics, transcriptomics and single-cell analyses have unveiled how epigenetic alterations - including DNA methylation, histone modifications, and RNA editing - dynamically regulate immune evasion and tumor progression. These findings have paved the way for novel therapies aimed at reversing epigenetic dysregulation and restoring immune surveillance. We evaluate promising epigenetic-targeting strategies in clinical development and propose key research directions to accelerate their translation into effective combination therapies. By linking fundamental research to clinical applications, this review aims to provide actionable insights for advancing precision medicine in DLBCL, with the ultimate goal of improving patient outcomes.