Death receptors (Fas receptor, TRAIL-R1, and TRAIL-R2) (DRs)

Death receptors, specifically Fas (CD95), TRAIL-R1 (DR4), and TRAIL-R2 (DR5), are transmembrane proteins belonging to the tumor necrosis factor receptor (TNFR) superfamily that initiate the extrinsic apoptosis pathway (UniProt P25445, O00220, O14763). These receptors are characterized by a cytoplasmic death domain that, upon engagement by ligands such as Fas ligand (FasL) or TRAIL, recruits adapter proteins like FADD to form the death-inducing signaling complex (DISC) (Ashkenazi & Dixit, 1998). This complex activates initiator caspases, primarily Caspase-8, leading to a proteolytic cascade that results in programmed cell death (Thorburn, 2004). In the context of immunotherapy, engineered high-affinity Natural Killer (haNK) cells are designed to exploit this pathway by expressing FasL and TRAIL on their surface to directly trigger apoptosis in tumor cells (ImmunityBio, 2024). This approach is intended to overcome tumor resistance to conventional therapies that rely on the intrinsic mitochondrial apoptotic pathway. However, the efficacy of targeting these receptors can be limited by the presence of decoy receptors (DcR1 and DcR2) or the upregulation of inhibitory proteins like c-FLIP within the tumor microenvironment (PubMed: 29038211). Clinical development of death receptor agonists has historically faced challenges such as hepatotoxicity, though cell-based delivery via haNK cells aims to provide a more localized and potent therapeutic effect.

Other names

CD95TNFRSF6Fas receptorDeath receptor 4DR4TNFRSF10ATRAIL-R1Death receptor 5DR5TNFRSF10BTRAIL-R2APO-1Apo-2

Activation of the extrinsic apoptotic pathway through ligand-induced receptor trimerization, recruitment of FADD, and subsequent activation of Caspase-8.