Cholangiocarcinoma (CCA) is a cancer of the bile duct epithelium, which is increasingly associated with chronic inflammation and/or cholestasis. In recent years, fibroblast growth factor (FGF) signaling has gained substantial interest in CCA with three U.S. Food and Drug Administration (FDA)-approved drugs currently available for targeted inhibition of FGF receptors (FGFRs). FGF signaling is implicated in various aspects of CCA tumorigenesis, influencing immune responses and correlating with less favorable therapeutic outcomes. Despite some progress in our understanding of the genetic underpinnings of CCA over the past decade, the contribution of patient-intrinsic germline variations implicated in FGF/FGFR signaling had not been systematically explored. Here, we explore the hypothesis that the dual impact of germline variants pleiotropically associated with the FGFR signaling pathway acts both as signals promoting tumorigenesis (tumor-intrinsic) and as shields protecting tumors from targeted immune response (tumor-extrinsic). This dualistic behavior sheds insights into the intricate interplay between genetic predisposition and pleiotropic factors in CCA pathogenesis, potentially impacting the prognosis of targeted therapies and immune checkpoint blockade therapies.