Cancer‐Associated Fibroblast‐Derived FGF7 Promotes Immune Escape in Oral Squamous Cell Carcinoma via JAK/STAT3‐Mediated PD‐L1 Expression

ABSTRACT Oral squamous cell carcinoma (OSCC) exhibits high recurrence rates, and immune escape within the tumor microenvironment is a critical barrier to effective therapy. This study investigates whether cancer‐associated fibroblast (CAF)‐derived FGF7 promotes immune escape in OSCC through JAK/STAT3 pathway‐mediated PD‐L1. Tumor and adjacent tissues from OSCC patients were analyzed for FGFF7 expression, and the correlations between FGF7 and clinicopathological features were analyzed. CAFs were isolated from OSCC, transfected with plasmids targeting FGF7, and assessed for activation markers, 3D spheroid formation, and epithelial‐mesenchymal transition (EMT) proteins. Co‐culture systems were established to evaluate the malignant behaviors of OSCC cells exposed to modified CAFs through proliferation, migration, invasion, and apoptosis assays. OSCC cells were co‐cultured with CD8 + T cells, followed by measurement of JAK/STAT3 phosphorylation, PD‐L1 expression, T‐cell activation markers, and immune‐related genes. In vivo effects were examined in xenograft models. FGF7 was overexpressed in OSCC tissues and cells, primarily originating from CAFs. FGF7 knockdown in CAFs suppressed activation markers, EMT, and malignant behaviors of OSCC cells. Mechanistically, FGF7 knockdown reduced JAK/STAT3 phosphorylation and PD‐L1 expression, impairing T‐cell cytotoxicity and antigen presentation. A specific STAT3 inhibitor completely reversed FGF7‐induced PD‐L1 upregulation. ChIP‐qPCR confirmed that STAT3 directly binds to the PD‐L1 promoter and activates its transcription. In vivo, CAF‐specific FGF7 knockdown attenuated tumor growth and collagen deposition while increasing CD8 + T‐cell infiltration and apoptosis. Combined FGF7 knockdown and anti‐PD‐L1 therapy synergistically enhanced these effects. CAF‐derived FGF7 drives immune escape and OSCC progression by upregulating PD‐L1 via JAK/STAT3 signaling.