FGFR pathway inhibition enhances PD-1 blockade and modulates antitumor immunity in colorectal cancer models

Abstract Immune checkpoint blockade (ICB) has demonstrated limited efficacy in microsatellite stable (MSS) colorectal cancer (CRC). The fibroblast growth factor receptor (FGFR) signaling pathway contributes to tumor immune evasion, yet its role in CRC remains insufficiently understood. We investigated the immunomodulatory effects of FGFR inhibition in combination with PD-1 blockade in murine CRC models. In vitro co-culture systems were used to evaluate T cell activation upon FGFR3 blockade. RNA sequencing and bioinformatics analyses, including The Cancer Genome Atlas (TCGA) dataset evaluation, were conducted to elucidate molecular mechanisms and clinical relevance. Combined FGFR inhibition and PD-1 blockade significantly reduced T cell exhaustion and promoted macrophage repolarization toward an antitumor phenotype. Transcriptomic profiling revealed upregulation of immune-related pathways and activation of immune-stimulatory genes. In vitro, FGFR3-specific monoclonal antibody treatment enhanced IFNg release following PD-1 blockade. Moreover, analysis of TCGA data demonstrated that high FGFR3 expression correlates with worse prognosis in CRC patients. Our findings suggest that FGFR pathway inhibition may enhance the efficacy of immune checkpoint blockade and provide a rationale for further investigation of FGFR-targeted combination strategies in MSS CRC.