Abstract

Background Microsatellite-stable colorectal cancer (MSS CRC) resists immune checkpoint inhibitors. FGF19's immunomodulatory role in MSS CRC remains unclear. Methods Bioinformatics analyzed FGF19 expression and CD8 + T-cell infiltration. CRC cells co-cultured with neutrophils (dHL-60) assessed chemotaxis and NET markers. LDH assay, ELISA, and CFSE staining measured CD8 + T-cell activity. CCK-8, EdU, Transwell, and flow cytometry assessed CRC phenotypes. Mouse model tested PD-1 antibody and FGFR4 inhibitor BLU-9931. Results FGF19 was upregulated in non-immunogenic MSS CRC, negatively correlating with CD8 + T cells. Elevated FGF19 enhanced neutrophil chemotaxis and NET release, inhibiting CD8 + T-cell cytotoxicity and proliferation while promoting malignant CRC behavior. Mechanistically, FGF19-FGFR4 signaling was associated with increased ERK pathway activity, elevated IL-8 levels, and NET formation. Blocking FGF19-FGFR4 enhanced PD-1 efficacy in MSS CRC. Conclusion The FGF19/ERK/IL-8 pathway contributed to NET formation in this model. Targeting this pathway represents a promising strategy to boost immunotherapy in MSS CRC.