Death receptor (Tumor necrosis factor receptor superfamily member 6, 10A, and 10B) (DR)

Death receptors, primarily the Fas receptor (Tumor necrosis factor receptor superfamily member 6) and TRAIL receptors (Tumor necrosis factor receptor superfamily member 10A and 10B), are critical mediators of the extrinsic apoptotic pathway (UniProt P25446, O00220, O14763). These receptors are expressed on the surface of various tumor cells and, when engaged by their respective ligands (FasL and TRAIL), initiate a signaling cascade that leads to programmed cell death. Effector immune cells, such as cytokine-induced killer (CIK) cells and gamma-delta (γδ) T cells, utilize the expression of FasL and TRAIL as a primary mechanism to eliminate malignant cells (PubMed: 31431114). Upon ligand binding, the receptors' intracellular death domains recruit the adapter protein FADD, forming the death-inducing signaling complex (DISC) and activating Caspase-8. While targeting these receptors with agonistic antibodies or recombinant ligands like Dulanermin has shown promise in preclinical models, clinical efficacy has been hampered by tumor resistance mechanisms, such as the upregulation of c-FLIP, and safety concerns like hepatotoxicity, particularly with Fas-targeted agents (PubMed: 19017547). Modern therapeutic approaches often involve combining death receptor agonists with sensitizing agents or using engineered cell therapies to provide localized, high-concentration ligand delivery.

Other names

Fas receptorCD95APO-1TNFRSF6TRAIL-R1DR4TNFRSF10ATRAIL-R2DR5TNFRSF10BApo-2Killer/DR5

Agonism of death receptors (Fas, DR4, DR5) triggers the extrinsic apoptotic pathway via recruitment of FADD and activation of Caspase-8.