Tumor necrosis factor receptor superfamily member 10B (TRAIL-R2) (TNFRSF10B)

Tumor necrosis factor receptor superfamily member 10B (TRAIL-R2), also known as Death Receptor 5 (DR5), is a cell surface receptor that initiates the extrinsic apoptotic pathway upon binding to the TNF-related apoptosis-inducing ligand (TRAIL) (UniProt: P57807). This interaction leads to the recruitment of the Fas-associated death domain (FADD) and pro-caspase 8, forming the death-inducing signaling complex (DISC) which activates the downstream caspase cascade (PubMed: 30610224). Gamma-delta (γδ) T cells are a unique subset of lymphocytes that exert potent anti-tumor activity by producing soluble TRAIL, which specifically binds to TRAIL-R2 on cancer cells to induce apoptosis while sparing normal tissues (PubMed: 29730544). Because TRAIL-R2 is frequently overexpressed in various malignancies, it has been extensively targeted by agonistic monoclonal antibodies and recombinant TRAIL variants in clinical trials. However, therapeutic success has been hindered by the presence of decoy receptors (TRAIL-R3 and TRAIL-R4) that sequester the ligand without inducing death signals, and by rare but severe hepatotoxicity associated with certain multivalent agonists (PubMed: 25824306). Current research focuses on next-generation multivalent agonists and combination therapies to overcome resistance mechanisms such as c-FLIP overexpression.

Other names

Death receptor 5DR5CD262KILLERTRICK2ZTNFR9TRAIL receptor 2TRAIL-R2

Agonism of the death receptor to trigger the extrinsic apoptotic pathway via formation of the death-inducing signaling complex (DISC).