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

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

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.

Figures
Products
Inhibitors & Agonists
Other Products