Exercise reduces hepatic pre-metastatic niche formation via TREM-1 signaling in kupffer cells.

Abstract

Tumor-derived exosomes contribute to the formation of a hepatic pre-metastatic niche (PMN) by activating Kupffer cells (KCs) and hepatic stellate cells (HSCs), thereby promoting metastatic seeding. Whether exercise modulates exosome-driven PMN formation and subsequent liver metastasis remains unclear. Eight-week-old male mice were randomized to sedentary (SED) and exercise training (ExT) groups. Mice were pre-educated with cancer-derived exosomes to induce a hepatic PMN and subsequently subjected to experimental liver metastasis model. Kupffer cells were isolated for transcriptomic and mechanistic analyses. Pharmacologic inhibition of TREM-1 signaling was performed to assess pathway-specific effects. Exercise training significantly attenuated hepatic PMN formation and reduced metastatic burden in exosome-educated mice. Exosome uptake by KCs was comparable between SED and ExT groups; however, ExT reduced KC inflammatory activation. Transcriptomic analysis identified downregulation of the TREM-1 signaling pathway in ExT KCs. Reduced TREM-1 activity was associated with diminished NF-κB activation in HSCs, decreased fibronectin deposition, and increased HSC apoptosis. Pharmacologic TREM-1 inhibition recapitulated key anti-metastatic effects observed with exercise. Exercise training attenuates tumor exosome-induced hepatic pre-metastatic niche formation through modulation of Kupffer cell inflammatory signaling, in part via suppression of TREM-1. Targeting TREM-1 signaling significantly reduces experimental liver metastasis and may represent a therapeutic approach that partially recapitulates the anti-metastatic effects of exercise. These findings support further investigation into exercise and innate immune modulation as strategies to influence early metastatic niche biology.