Tumor necrosis factor superfamily member 14 (TNFSF14), also known as CD258 and LIGHT, is a cell surface type II transmembrane protein that is expressed as a homotrimer. The extracellular region can be cleaved to generate a soluble cytokine. TNFSF14 is a ligand for the receptors herpesvirus entry mediator (HVEM) and lymphotoxin receptor (LTR). TNFSF14 is expressed on activated NK cells, activated T cells, activated monocytes, immature DCs, and mast cells. TNFSF14 interactions with HVEM induce potent co-stimulatory signaling in T cells and trigger NK cells to produce IFN-gamma via NF-kappaB RelA/p50 pathway signaling. TNFRSF14 produced by tumor-sensing NK cells aids in DC maturation, enabling de novo anti-tumor adaptive immune responses. TNFSF14-HVEM interactions are considered the main drivers of anti-tumor immune responses, whereas TNFSF14-LTR interactions have been characterized as maintaining the infrastructure that supports the anti-tumor response via lymphoid development and cancer cells susceptibility to the immune response. TNFSF14 induces the normalization of tumor vasculature, sensitizes tumor cells to IFN-gamma-mediated apoptosis, and results in a more inflamed tumor microenvironment (TME). Due to its effects on the TME and anti-tumor immune cell responses, TNFSF14 is being investigated as a target for immunotherapeutic intervention in cancer. TNFSF14 has also been implicated in the development and pathogenesis of inflammatory bowel disease and airway remodeling leading to asthma.
