Tumor necrosis factor-like weak inducer of apoptosis–Fibroblast growth factor-inducible 14 protein–protein interaction (TWEAK–Fn14 PPI)

The TWEAK–Fn14 protein–protein interaction is a critical signaling axis composed of the ligand Tumor Necrosis Factor-like Weak Inducer of Apoptosis (TWEAK; TNFSF12) and its highly inducible receptor, Fibroblast Growth Factor-inducible 14 (Fn14; TNFRSF12A) (Winkles, 2008, Nature Reviews Drug Discovery). Under physiological conditions, Fn14 expression is low, but it is rapidly upregulated following tissue injury or in chronic disease states, where it mediates cellular responses such as proliferation, migration, and the secretion of pro-inflammatory cytokines (Burkly et al., 2007, Cytokine & Growth Factor Reviews). This interaction activates multiple intracellular pathways, most notably the canonical and non-canonical NF-κB pathways, which drive inflammation and tissue remodeling (Zheng et al., 2016, Frontiers in Immunology). In oncology, the TWEAK–Fn14 axis is frequently hijacked to promote tumor growth, metastasis, and resistance to apoptosis, particularly in solid tumors like glioblastoma and breast cancer (Cherry et al., 2015, Molecular Cancer Therapeutics). Therapeutic strategies have primarily utilized monoclonal antibodies to disrupt this interaction, either by neutralizing the TWEAK ligand or by targeting the Fn14 receptor to block signaling or induce antibody-dependent cellular cytotoxicity (ADCC) (Yao et al., 2011, Journal of Biological Chemistry). Despite promising preclinical data in models of autoimmune disease and cancer, clinical trials have faced hurdles regarding efficacy and the identification of optimal patient populations (Culp et al., 2010, Clinical Cancer Research).

Other names

TNFSF12–TNFRSF12A interactionTWEAK–Fn14 axisTWEAK–CD266 interactionTWEAK–Fn14 signaling complex

Antagonism of the TWEAK–Fn14 interaction using monoclonal antibodies to block ligand-receptor binding, thereby inhibiting downstream canonical and non-canonical NF-κB signaling pathways and reducing pro-inflammatory cytokine production.