Molecular Landscape of Classical Hodgkin Lymphoma: From Genetic Lesions to Biologically Defined Subtypes

Hodgkin lymphoma (HL) represents a unique lymphoid malignancy characterized by the presence of rare malignant Hodgkin and Reed–Sternberg (HRS) cells embedded within a highly complex and immunologically active tumor microenvironment. Over the past decade, advances in genomic and transcriptomic technologies have substantially refined the understanding of HL pathogenesis. Recurrent genetic alterations affecting key oncogenic pathways, including NF-κB, JAK/STAT, and PI3K/AKT signaling, cooperate with widespread mechanisms of immune evasion to sustain tumor cell survival and proliferation. Epstein–Barr virus infection contributes to lymphomagenesis in a significant subset of cases by providing surrogate survival signals, modulating immune interactions and targeting the telomere-shelterin complex through LMP1. In parallel, emerging evidence highlights the central role of the tumor microenvironment, which actively supports malignant cell growth through direct cellular interactions, cytokine signaling, and metabolic and immune-regulatory mechanisms. Recent studies using circulating tumor DNA (ctDNA) profiling and single-cell approaches have enabled non-invasive genomic characterization and revealed biologically distinct molecular subgroups, further underscoring the interplay between tumor genetics and immune contexture. These insights are reshaping disease classification and opening new avenues for biomarker-driven therapeutic strategies. A deeper integration of molecular, immunological, and microenvironmental features will be crucial to optimize risk stratification and to develop more precise and less toxic treatments for patients with HL.