Sympathetic immunomodulation suppresses liver metastasis by maintaining the balance between norepinephrine concentration and the α2a/β2-AR ratio.

The sympathetic nervous system (SNS) plays a crucial role in chronic liver diseases, but its function, particularly in terms of the underlying mechanisms of liver metastasis, remains unclear. Here, we reported that hepatic sympathetic nerve activity increases in the early stage of metastasis and was accompanied by a moderate increase in norepinephrine (NE). Unexpectedly, NE had a dose-dependent effect on colorectal liver metastasis. Only daily administration of low-dose NE could maintain NE at a moderate concentration in the liver during this early phase significantly suppressed metastatic tumor growth. Conversely, extremely low NE concentrations (induced by 6-hydroxydopamine, 6-OHDA) or high-dose NE prompted liver metastasis. Single-cell RNA sequencing (scRNA-seq) demonstrated that NE modulated monocyte recruitment and M2 macrophage polarization through the CCL2-CCR2 signaling axis and influenced the immunosuppressive effects of myeloid-derived suppressor cells (MDSCs) on T cells: low-dose NE inhibited monocyte recruitment and M2 macrophage polarization and relieved the immunosuppressive effects of MDSCs on T cells, whereas extremely low- and high-dose NE supplementation had the opposite effects. Further investigations confirmed that these biological effects were closely associated with the NE-mediated expression ratio of α2a-adrenergic receptor to β2-adrenergic receptor (α2a-AR/β2-AR). Specifically, at moderate NE concentrations, a high α2a-AR/β2-AR expression ratio was correlated with antitumor effects. Collectively, these findings reveal that the SNS mediates U-shaped effects on liver metastasis in an α2a-AR/β2-AR ratio-dependent manner, highlighting moderate sympathetic activation as a potential therapeutic strategy to inhibit the progression of liver metastasis.