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

Abstract

Colorectal cancer mortality is primarily driven by hepatic metastasis, with 50-60% of patients relapsing following liver metastasis resection due to micro-metastases or tumor cell dissemination. Surgery-induced immunologic disturbances contribute to liver recurrence. Exercise modulates immune responses, yet its role in surgical stress-promoted liver metastasis remains unclear. We demonstrate that 4 weeks of preoperative exercise (PEx) limits tumor growth in a murine model of surgical stress-promoted liver metastasis by shifting Kupffer cells toward an anti-tumor phenotype. PEx promotes Kupffer cell cytotoxic cytokines release and enhances CD8⁺ T cells recruitment and activation via the CXCL9-CXCR3 axis. Elevated CXCL9 levels are observed in murine and patient sera post exercise, with Kupffer cells identified as the primary source. Furthermore, exercise-induced butyrate accumulation in Kupffer cells inhibits histone deacetylase 3 activity, promoting CXCL9 expression. These findings suggest that PEx may serve as a non-invasive strategy to reduce recurrence and provide potential targets for exercise-mimetic therapies.