More than 20 years ago, a new secreted ligand of the tumor necrosis factor (TNF) family was identified in mouse peritoneal macrophage, human tonsil and fetal liver. However, in contrast to TNF, TWEAK induced only weakly apoptosis in a panel of cell types such as hematopoietic cells, fibroblasts and cancer cells, and was thus named TWEAK for “tumor necrosis factor-like weak inducer of apoptosis”. TWEAK displays two forms, membrane-bound or soluble. As TNF, TWEAK activates nuclear factor kappa-light-chain-enhancer of activated B cells (NF-B) pathway and thereby inflammatory responses. Meanwhile, and independently of TWEAK, fibroblast growth factor-inducible 14 (Fn14), a type I transmembrane protein was identified as a modulator of fibroblast adhesion and migration. Soon after, it was discovered in endothelial cells (ECs) for its role in angiogenesis as the receptor of TWEAK. While Fn14 was already known for its hepatic functions including regeneration and cancer, i.e. hepatocellular carcinoma (HCC) [1], the role of TWEAK/Fn14 signaling in cholangiocarcinoma (CCA), the second more frequent liver cancer after HCC, was unknown so far. In an elegant work, Dwyer et al. [2] highlighted essential functions of TWEAK/Fn14 in intrahepatic CCA (iCCA), the anatomical subtype of CCA arising above the second-order bile ducts. In iCCA, TWEAK promotes the development of the tumor niche sustaining tumor initiation and progression, which could pave the way for a potential treatment of iCCA patients since TWEAK/Fn14 pathway is a “druggable” target.