Tumor necrosis factor receptor superfamily member 10A (DR4), Tumor necrosis factor receptor superfamily member 10B (DR5), and Tumor necrosis factor receptor superfamily member 6 (Fas) (DR4, DR5, and Fas)

Tumor cell death receptors, specifically Fas (CD95), Death Receptor 4 (DR4), and Death Receptor 5 (DR5), are transmembrane proteins belonging to the tumor necrosis factor (TNF) receptor superfamily that initiate the extrinsic apoptotic pathway [UniProt: P25445, O00220, O14763]. These receptors are characterized by an intracellular death domain (DD) that, upon ligation by Fas Ligand (FasL) or TNF-related apoptosis-inducing ligand (TRAIL), recruits adapter proteins like FADD to form the death-inducing signaling complex (DISC) [Guicciardi & Gores, 2009]. This complex activates pro-caspase-8, triggering a downstream caspase cascade that results in rapid cell death. In modern oncology, iPSC-derived natural killer (NK) cells are being developed as therapeutic agents because they can be engineered to stably express FasL and TRAIL, allowing them to engage these death receptors on tumor cells effectively [Li et al., 2018]. While targeting these receptors offers a direct mechanism to bypass some internal apoptotic blocks in cancer cells, therapeutic development has been hampered by challenges such as severe hepatotoxicity associated with systemic Fas activation and the presence of decoy receptors (DcR1/DcR2) on tumor cells that compete for ligand binding [Ashkenazi, 2008]. Consequently, current research focuses on more selective DR4/DR5 agonists and cell-based delivery methods to maximize anti-tumor efficacy while minimizing systemic side effects.

Other names

Death receptor 4Death receptor 5Fas receptorCD95TNFRSF10ATNFRSF10BTNFRSF6TRAIL-R1TRAIL-R2APO-1KILLERTRICK2

Agonism of death receptors (DR4, DR5, or Fas) triggers the extrinsic apoptotic pathway by inducing the formation of the death-inducing signaling complex (DISC), leading to caspase activation and cell death.