Tumor necrosis factor receptor superfamily member 10A and 10B (Death receptor 4 and 5) (TNFRSF10A/TNFRSF10B)

Tumor necrosis factor receptor superfamily member 10A (DR4) and 10B (DR5) are transmembrane proteins that trigger the extrinsic apoptosis pathway upon binding to the TNF-related apoptosis-inducing ligand (TRAIL) [UniProt: P50591, O14763]. These receptors are frequently overexpressed in a variety of malignancies, including colorectal, lung, and pancreatic cancers, while showing limited expression in most normal tissues, making them ideal targets for selective cancer therapy [PubMed: 11071301]. When TRAIL binds to DR4 or DR5, it induces receptor trimerization and the formation of the death-inducing signaling complex (DISC), which activates caspase-8 and initiates a cascade leading to cell death [StatPearls: Apoptosis]. Umbilical cord tissue-derived natural killer (UTD-NK) cells are a potent source of immunotherapy that naturally or through engineering express high levels of membrane-bound TRAIL, allowing them to directly engage these receptors on tumor cells [PubMed: 33806174]. Therapeutic development has focused on recombinant TRAIL (e.g., dulanermin) and agonistic antibodies (e.g., mapatumumab, conatumumab), though clinical success has been limited by short half-lives and tumor resistance mechanisms [PubMed: 24591136]. Current research into UTD-NK cells aims to overcome these limitations by providing a continuous, cell-mediated delivery of TRAIL directly to the tumor microenvironment.

Other names

DR4DR5TRAIL-R1TRAIL-R2APO2CD261CD262KILLERTRICK2Tumor necrosis factor receptor superfamily member 10ATumor necrosis factor receptor superfamily member 10B

Agonism of DR4 and DR5 receptors by TRAIL (delivered via UTD-NK cells or other agents) triggers receptor trimerization and formation of the Death-Inducing Signaling Complex (DISC), activating the extrinsic apoptotic pathway.