Background <p>The LEAP-002 study showed that pembrolizumab plus lenvatinib did not provide statistically significant prognostic improvement over lenvatinib monotherapy in advanced hepatocellular carcinoma (HCC). This study investigated the potential protective role of high fibroblast growth factor receptor 4 (FGFR4) expression, a therapeutic target of lenvatinib, in immunotherapy for HCC.</p> Methods <p>The Kaplan Meier plotter database was used to assess the impact of FGFR4 expression on immunotherapy outcomes; the TCGA-LIHC dataset was analyzed for correlations between FGFR4 expression, immune checkpoint gene profiles, and immune cell infiltration; and single-cell RNA sequencing (scRNA-seq) data from GSE149614 were used to examine interactions between high- and low-FGFR4 cancer cell subpopulations and immune cells. Validation was performed in tumor specimens from HCC patients treated with lenvatinib in combination with PD-1 inhibitors.</p> Results <p>High FGFR4 expression predicted favorable immunotherapy outcomes and correlated with immune checkpoint genes such as PCDH1 and CD274, along with reduced M2 macrophage infiltration in TCGA-LIHC. scRNA-seq analysis showed FGFR4 enrichment in cancer cells, with high-FGFR4 cancer cells displaying a unique CXCL1–CXCR2 signaling axis with macrophages. High FGFR4 expression activated the MAPK pathway and increased JUN(+) transcriptional activity, showing a significant positive correlation with CXCL1 levels. In HCC patients treated with lenvatinib plus PD-1 inhibitors, high FGFR4 expression was linked to enhanced M1 macrophage polarization and elevated PD-L1 expression, whereas low FGFR4 expression correlated with better clinical outcomes.</p> Conclusion <p>FGFR4-high expression is associated with an immune-responsive phenotype in HCC and predicts inferior efficacy of lenvatinib plus PD-1 blockade.</p>