Beta-2 microglobulin in lymphoma

Abstract

Lymphomas are heterogeneous hematologic malignancies characterised by the abnormal proliferation of lymphocytes. β₂-Microglobulin (β₂M) functions both as a structural subunit of primary histocompatibility complex class I (MHC I) and as a circulating biomarker with established diagnostic and prognostic significance. Serum β₂M > 2.5 mg/L is elevated in 60 % of mantle cell lymphoma and in > 50 % of advanced-stage diffuse large B-cell lymphoma, correlating with higher tumor burden, International Prognostic Index scores, and inferior survival; cerebrospinal fluid β₂M enhances central nervous system lymphoma diagnosis with 97 % sensitivity and specificity. Mechanistically, β₂M stabilizes MHC I to enable CD8⁺ T-cell antigen presentation and, when shed, activates JAK/STAT and NF-κB pathways that drive tumor proliferation and immune evasion. Preclinical strategies targeting these β₂M-driven signals such as anti-β₂M antibodies combined with proteasome inhibitors demonstrate enhanced cytotoxicity in resistant models. Advanced three-dimensional scaffold culture platforms preserve β₂M-tumour-immune interactions, allowing for the investigation of matrix stiffness effects on signalling. Emerging mechanotherapy approaches leverage extracellular matrix rigidity to modulate β₂M-related pathways and sensitize lymphoma cells to therapy. The remaining challenges include assay standardization, cohort variability, and lack of prospective validation of β₂M-based indices. Future efforts should focus on harmonising β₂M measurement methods and integrating mechanistic insights into refined risk stratification and therapeutic strategies.