Norepinephrine promotes colorectal cancer liver metastasis via mechanisms dependent on Kupffer cells

The mechanisms underlying colorectal cancer liver metastasis (CRLM) remain incompletely understood. Increasing evidence suggests that stress-associated catecholamines may influence tumor progression. However, how norepinephrine (NE) influences the hepatic immune microenvironment during CRLM progression remains poorly characterized. In this study, we investigated the effects of NE on liver-resident macrophages during CRLM progression by integrating patient-based clinical analyses, single-cell transcriptomic profiling, and mechanistic in vivo and in vitro experiments. Clinically, patients with CRLM exhibited higher levels of psychological distress and increased circulating NE and CXCL12 compared with patients without liver metastasis. Anxiety scores were positively correlated with circulating NE and CXCL12. Single-cell RNA sequencing of CRLM lesions revealed macrophages as the predominant immune cell population with enriched expression of CXCL12, IL-10, and ADRB2, which encodes the β2-adrenergic receptor (β2-AR). In the hepatic context, this population was predominantly composed of Kupffer cells (KCs). In murine CRLM models, exogenous NE administration increased hepatic metastatic burden and KC accumulation, whereas selective KC depletion abrogated the pro-metastatic effects of NE. Mechanistically, NE promoted M2-like polarization of KCs in vitro through β2-AR-dependent activation of the PI3K/Akt pathway and altered their secretory profile. Consistently, NE-conditioned KCs enhanced colorectal cancer cell migration via CXCL12, an effect that was attenuated by pharmacological inhibition of β2-AR signaling or blockade of the CXCL12-CXCR4 axis. Overall, this study identifies a norepinephrine-driven neuroimmune mechanism in which β2-AR signaling reprograms KCs toward a pro-metastatic phenotype, thereby facilitating CRLM.