Inhibition of neutrophil extracellular traps via the FGF19/ERK/IL-8 axis enhances immune therapy in MSS colorectal cancer

  • Clin Immunol. 2026 Apr:284:110664. doi: 10.1016/j.clim.2026.110664.
Yiyang Wu  1 ,  Jintian Wang  2 ,  Pengcheng Wang  2 ,  Qiwei Chen  3 ,  Jing Jia  3 ,  Yan Liu  3 ,  Yao Chen  3 ,  Kai Ye  4
Affiliations
  • 1. Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou City, Fujian Province, China; Department of Gastrointestinal Surgery, First Hospital of Quanzhou Affiliated to Fujian Medical University, Quanzhou City, Fujian Province, China.
  • 2. Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou City, Fujian Province, China.
  • 3. Department of Gastrointestinal Surgery, First Hospital of Quanzhou Affiliated to Fujian Medical University, Quanzhou City, Fujian Province, China.
  • 4. Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou City, Fujian Province, China. Electronic address: [email protected].
PMID: 41565192 DOI: 10.1016/j.clim.2026.110664
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.

Keywords
CD8(+) T cells; ERK; FGF19/FGFR4; Immune response; MSS CRC.
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