Hodgkin lymphoma (HL) is an uncommon form of tumor that primarily occurs in young adults, although it can also occur in older individuals, albeit less frequently. It is characterized by its early onset, a unique tumor microenvironment rich in immune effector cells, and a remarkably low proportion of malignant cells. A defining characteristic of HL is the existence of Hodgkin and Reed-Sternberg cells (HRSC), large, multinucleated cells derived from B lymphocytes (typically found within a microenvironment abundant in immune effector cells, which are of central importance to disease pathophysiology [1], [2]. Worldwide, HL represents approximately 0.4 % of all newly diagnosed cancer cases and around 0.2 % of cancer-related mortality [3]. The diversity of molecular characteristics within HL subtypes, such as nodular sclerosis and mixed cellularity, allows one to identify the specific genetic drivers of subtypes (although difficult), and hence, there is promise of subtype-specific therapy [4].

The relevance of advanced HL has increased following the advent of therapies that target specific molecular markers, such as PD-1/PD-L1 inhibitors, nivolumab, and CD30-targeted therapies, including brentuximab vedotin. Although a wide range of standard treatments achieves cure rates exceeding 80 % in the early stages of HL, managing advanced or relapsed HL cases remains a significant challenge, highlighting the necessity for further molecular research [5]. The notably greater risk seen in identical twins indicates a genetic factor in the disease. Additionally, specific polymorphisms among genes responsible for regulating immune functions have been linked to an increased likelihood of developing HL [6]. Classical Hodgkin lymphoma (cHL) typically arises in the supradiaphragmatic lymph nodes and progressively spreads to adjacent lymph nodes. It eventually involves the spleen before spreading to extranodal sites, such as the bone marrow, bones, liver, and lungs. The treatment is based on conventional staging, achieving a rate of over 90 % in curing limited-stage disease and approximately 80 % in advanced-stage disease [1]. The HRSC consistently express CD30 and may variably express CD15, while typical B-cell marker expression is often reduced [7]. This neoplasm, known as HRSC, is responsible for malignancy-driving cells and exhibits distinctive characteristics. These include their rarity compared to the abundant reactive microenvironment, the diminished expression of B-cell phenotype markers, their ability to evade the immune system, and the activation of critical signaling cascades, such as the JAK/STAT, MAPK/ERK, and NF-κB pathways.

Despite the challenges in segregating and studying HRSC in vivo, evidence suggests that both canonical and noncanonical NF-κB pathways appear to be active, underscoring the critical role in the pathogenesis of the HL pathway [8]. Genetic and epigenetic alterations in HRSC result in consistent activation of the NF-κB pathway that is instrumental in cellular survival and immunity in HL (Fig. 1) [9]. NF-κB in HRSC stays persistently active because of genetic mutations in such factors as TNFAIP3 and NFKBIA, and environmental interactions for tumor survival and immune escape [10], [11]. This review focuses on the molecular foundations of HL, with an emphasis on the impact of B lymphocyte mutations and dysregulation of the NF-κB pathway on disease progression, and identifies potential therapeutics, including NF-κB inhibitors and epigenetic modulators.