The sympathetic nervous system (SNS) innervates metastatic targets including lung and lymph node. Stress-induced SNS signalling promotes cancer progression. However, the impact of neural signaling on the tumour microenvironment has been largely overlooked. Using a novel method to directly visualise lymph flow in vivo, we demonstrated that direct SNS signalling promotes flow through collecting lymphatic vessels. Using preclinical models we show that chronic stress drives signalling through a tumour neural-inflammatory (TNI) axis to restructure intratumoural and draining lymphatic vessels, leading to increased lymphatic dissemination and metastasis from primary tumours. Beta-blockers and COX inhibitors effectively inhibited vascular remodelling and lymph node metastasis in preclinical models and cancer patients. These data highlight the important role of chronic stress in cancer progression and identify a TNI axis as a promising target for novel anti-cancer therapies. Further, we present clinical data that supports the impact of acute anaesthesia-induced sympatholysis on lympthatic flow, which may have a role in modulating the acute stress of cancer surgery and potential risk of cancer recurrence.