The Epigenetic Architecture of Classical Hodgkin Lymphoma: Lineage Erasure, Immune Escape, and Therapeutic Reprogramming

Classical Hodgkin lymphoma (cHL) is distinguished by a rare population of Hodgkin and Reed–Sternberg (HRS) cells that has largely extinguished its germinal center (GC) B-cell identity while maintaining survival, immune escape, and dependence on a highly organized tumor microenvironment (TME). This narrative review examines how interacting epigenetic mechanisms construct and stabilize this malignant state and evaluates whether it can be therapeutically reprogrammed. The relevant mechanistic and clinical literature available through 2026 was synthesized, encompassing lineage factor disruption, DNA methylation, histone modifications, Polycomb repression, chromatin-remodeling lesions, non-coding RNAs, antigen presentation, immune checkpoint regulation, and epigenetic therapies in cHL. Lineage erasure appears to be an actively maintained program produced by promoter hypermethylation, histone deacetylation, Polycomb-associated repression, altered histone demethylase activity, transcription factor antagonism, and somatic lesions affecting chromatin regulators. These mechanisms coexist with structural and transcriptional alterations involving antigen presentation and programmed death ligand 1/programmed death ligand 2 (PD-L1/PD-L2), while non-coding RNAs and extracellular vesicles provide an additional regulatory layer connecting HRS cells with immune and stromal components of the TME. Epigenetic repression is heterogeneous in its reversibility: partially methylated or deacetylated loci may remain pharmacologically responsive, whereas densely methylated, Polycomb-associated, or genetically entrenched states are less likely to be restored through isolated interventions. Histone deacetylase (HDAC) and DNA methyltransferase (DNMT) inhibitors can nevertheless alter tumor- and immune-related programs, supporting combinations with PD-1 blockade. Complete restoration of a physiological B-cell epigenome is unlikely; however, the HRS state remains therapeutically modifiable. Epigenetic therapy may therefore be most effective when used to reduce state stability and increase immune visibility rather than to achieve complete lineage reconstitution.