Tumor necrosis factor receptor 1-Fas chimeric receptor (TNFR1-Fas)

The TNF-alpha/TNFR1-Fas chimeric receptor is an engineered therapeutic construct designed to hijack inflammatory signaling for the purpose of anti-angiogenic therapy. It typically comprises the extracellular ligand-binding domain of Tumor Necrosis Factor Receptor 1 (TNFR1) and the transmembrane and intracellular death domains of the Fas receptor (CD95). In the context of cancer therapy, this receptor is often delivered via gene therapy (such as VB-111) using promoters like PPE-1-3x that are specifically active in angiogenic endothelial cells. By expressing this chimera on the surface of proliferating endothelial cells within a tumor, the therapy converts the high levels of circulating or local TNF-alpha—which would otherwise promote tumor growth or inflammation—into a potent pro-apoptotic signal. Upon binding TNF-alpha, the TNFR1-Fas complex clusters and activates the extrinsic apoptotic pathway via the Fas death domain, leading to the selective collapse of the tumor's blood supply. This approach aims to starve the tumor of nutrients while minimizing systemic toxicity by restricting receptor expression to the neovasculature.

Other names

TNFR1-Fas chimeraTNFR1/Fas death receptorTNF-alpha/TNFR1-Fas complexTNFRSF1A-FAS fusion protein

The chimeric receptor consists of the extracellular domain of TNFR1 fused to the intracellular signaling domain of Fas. When expressed on angiogenic endothelial cells, it binds circulating TNF-alpha, which normally promotes inflammation or survival, and instead triggers the Fas-mediated apoptotic pathway, leading to the selective destruction of tumor-associated blood vessels.