Tumor-Associated Sympathetic Nerves Promote the Progression of Epstein-Barr Virus-Positive Diffuse Large B-Cell Lymphoma.

Epstein-Barr virus-positive (EBV(+)) diffuse large B-cell lymphoma (DLBCL) exhibits a poorer prognosis with limited treatment options. Although recent evidence indicates that the peripheral nervous system is associated with tumor progression, its role in EBV(+)DLBCL remains poorly understood. In the cohort, patients with EBV⁺DLBCL exhibit significantly shorter overall survival (OS). Two EBV(+)DLBCL cell lines are established and characterized. Although cell proliferation does not differ significantly in vitro, tumors derived from EBV(+) DLBCL cells demonstrate accelerated growth compared to their parental counterparts in mouse models. Mechanistically, transcriptome analysis reveals the upregulation of axonogenesis-related genes and pathways in EBV(+)DLBCL tumors. Immunostaining confirms increased nerve fiber infiltration in SUDHL6-EBV xenografts and enhance neurite outgrowth from dorsal root ganglia co-cultured with EBV(+)DLBCL cells. Both in vitro and in vivo experiments show that sympathetic nerves promote tumor growth via β2-adrenergic receptors (β2ARs), which are attenuated by selective β2AR blockers. Clinically, EBV⁺DLBCL patient samples show more sympathetic nerve fibers and higher β2AR expression, both of which are associated with poorer survival. Furthermore, a meta-analysis suggests that beta-blocker use is linked to a reduced risk of cancer-specific mortality. Together, these findings suggest that sympathetic nerve innervation drives the progression of EBV(+)DLBCL via β2ARs, highlighting a potential therapeutic target.