Fibroblastic reticular cell–derived HGF orchestrates sympathetic nerves in tumor-induced lymph node remodeling and metastasis

Lymph nodes (LNs) are critical peripheral immune organs extensively innervated by both sympathetic and sensory nerves. During tumor metastasis, LNs undergo significant structural remodeling and enlargement; however, the role of neural innervation in this process remains unclear. Here, using whole-organ three-dimensional (3D) imaging, we observed pronounced elongation and increased branching specifically in sympathetic nerve fibers, but not sensory nerves, during tumor-induced LN enlargement (TLNE), suggesting adaptive neural remodeling. Single-nucleus RNA sequencing further revealed activation of fibroblastic reticular cells (FRCs) during TLNE, characterized by enriched neuro-related signaling pathways and substantial secretion of hepatocyte growth factor (HGF). Functional validation using targeted HGF inhibitors and adeno-associated virus (AAV)-mediated HGF silencing confirmed that FRC-derived HGF critically drives sympathetic nerve growth. Additionally, both HGF inhibition and sympathetic nerve denervation significantly reduced TLNE and tumor-induced LN metastasis, highlighting the importance of adaptive sympathetic innervation in tumor-associated LN remodeling. These findings identify a previously unrecognized FRC-HGF-sympathetic nerve axis and propose neural regulation as a potential therapeutic strategy for tumor-induced LN metastasis.