TNFRSF12A (tumor necrosis factor receptor superfamily member 12A), also known as FN14 or TWEAK receptor, is a cell surface protein encoded by the TNFRSF12A gene. It belongs to the tumor necrosis factor receptor (TNFR) superfamily and plays roles in regulating cellular processes such as survival, proliferation, apoptosis, and inflammation. FN14 is minimally expressed in healthy tissues but is upregulated in pathological conditions, including cancers, fibrotic disorders, and neurodegenerative diseases. Its activation primarily occurs through binding to its ligand TWEAK (TNF-like weak inducer of apoptosis), triggering downstream signaling pathways like NF-κB and MAPK, which drive pro-inflammatory and tissue-remodeling responses.
Antibodies targeting TNFRSF12A are research tools used to study its expression, signaling mechanisms, and therapeutic potential. In cancer, FN14 overexpression correlates with tumor progression, metastasis, and resistance to therapy, making it a biomarker and therapeutic target. Anti-TNFRSF12A antibodies are being explored to block TWEAK/FN14 interactions, inhibit tumor growth, or deliver cytotoxic agents in antibody-drug conjugates (ADCs). In fibrosis, neutralizing antibodies may attenuate FN14-mediated fibroblast activation. However, challenges remain in optimizing specificity and minimizing off-target effects. Current research focuses on preclinical models and early-phase clinical trials to evaluate safety and efficacy, with potential applications in oncology, fibrotic diseases, and chronic inflammation.