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 EBVDLBCL remains poorly understood. In the cohort, patients with EBV⁺DLBCL exhibit significantly shorter overall survival (OS). Two EBVDLBCL 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 EBVDLBCL tumors. Immunostaining confirms increased nerve fiber infiltration in SUDHL6-EBV xenografts and enhance neurite outgrowth from dorsal root ganglia co-cultured with EBVDLBCL 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 EBVDLBCL via β2ARs, highlighting a potential therapeutic target.