biostudies-literatureHuang SNatural Science Foundation of ChinaNational Key R&D Program of ChinaGuangzhou Basic and Applied Basic Research SchemeBeijing Xisike Clinical Oncology Research FoundationNational Natural Science Foundation of ChinaNatural Science Foundation of Guangdong ProvinceNational Key Research and Development Program of Chinae13580https://www.ebi.ac.uk/biostudies/studies/S-EPMC12412552biostudies-literatureUnknown12(33)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.Advanced science (Weinheim, Baden-Wurttemberg, Germany)Tumor-Associated Sympathetic Nerves Promote the Progression of Epstein-Barr Virus-Positive Diffuse Large B-Cell Lymphoma.PMC124125522024A1515012975Y‐SYBLD2022MS‐0142823019752023YFC34045002023A04J17653227097182070215822220552024A151501115082003859Y-SYBLD2022MS-0142Liu HXia YCai QHuang SYang LZhuang DBi ALei DNie MWang YZhang PfalseTumor-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.2025-01-01T00:00:00Z2025 Sep2026-05-29T22:23:28.435Z2026-04-08T06:14:34.736ZS-EPMC124125524048831910.1002/advs.202413580