Preoperative exercise induces anti-tumor Kupffer cells to prevent surgical stress-promoted colorectal cancer liver metastasis 3986

Abstract Description Introduction Surgery-induced immunologic disturbances contribute to colorectal cancer liver metastases (CRLM) recurrence. Exercise modulates immune responses, yet its role in surgical stress-promoted CRLM is unclear. This study explores how preoperative exercise therapy (PEx) mitigates surgical stress-promoted CRLM through hepatic immune reprogramming. Methods 8-week-old mice underwent moderate-intensity treadmill exercise (12.5 m/min, 60 min/day, 5 days/week) for 4 weeks before MC38 tumor cell injection via the portal vein. Surgical stress was induced through partial liver ischemia-reperfusion (I/R). Hepatic infiltrating immune cells were analyzed using single-cell RNA sequencing (scRNA-seq). The role of Kupffer cells (KCs) was evaluated using diphtheria toxin-mediated depletion and adoptive transfer. Results PEx significantly reduced CRLM and reprogrammed KCs toward an anti-tumor phenotype. scRNA-seq revealed that PEx enhanced CXCL9 expression in KCs, which recruited CXCR3+CD8+ T cells and boosted their cytotoxic function. Increased CXCL9 was observed in both murine and patient serum after PEx and was associated with butyrate-mediated inhibition of histone deacetylase 3 in KCs. Conclusion PEx mitigates surgical stress-promoted CRLM by reprogramming KCs to recruit and activate CD8+ T cells via the CXCL9-CXCR3 axis. These findings highlight PEx as a promising strategy to improve surgical outcomes, with potential pharmacological applications for exercise-intolerant patients. Funding Sources NIH-R01-CA214865 UVA Comprehensive Cancer Center “IDEA-Cancer pilot award” UVA Comprehensive Cancer Center “Cancer Therapeutics (CRX) pilot award” Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)