FGFR2 fusion-driven CXCL3 downregulation attenuates neutrophil recruitment in intrahepatic cholangiocarcinoma

FGFR2 fusion is a common alteration in malignancies, including intrahepatic cholangiocarcinoma (iCCA). While FGFR2 fusion has oncogenic properties, iCCA patients harboring this alteration demonstrate favorable prognosis, remaining a paradox. Here, we delineated the transcriptomic landscape of FGFR2 fusion-positive iCCA. We observed transcriptional features related to PI3K-AKT signaling in tumor cells and reduced neutrophil infiltration, particularly of the PD-L1⁺ neutrophil subtype. Mechanistically, FGFR2 fusion was associated with reduced H3K27ac enrichment at the CXCL3 promoter and decreased CXCL3 expression in tumor cells, which may contribute to impaired neutrophil recruitment to tumor tissues. In preclinical models, pharmacological FGFR inhibition increased CXCL3 levels and neutrophil infiltration. Combining neutrophil blockade with clinically available FGFR inhibitors enhanced antitumor activity. In conclusion, this study provides mechanistic insights into the paradox between the oncogenic properties of FGFR2 fusion and favorable clinical outcomes in FGFR2 fusion-positive iCCA, and suggests a potential strategy to optimize FGFR2-targeted therapies.