Tumor necrosis factor-related apoptosis-inducing ligand receptor (TRAIL receptor (Death Receptor 4 [DR4]/Death Receptor 5 [DR5]))

Tumor necrosis factor-related apoptosis-inducing ligand receptors (TRAIL receptors) are members of the TNF receptor superfamily comprising cell-surface death receptors DR4 (TRAIL-R1) and DR5 (TRAIL-R2), as well as decoy receptors (DcR1/TRAIL-R3, DcR2/TRAIL-R4, OPG). These receptors bind the trimeric TRAIL ligand — a cytokine with structural homology to FasL and TNF-α — and upon ligand-induced trimerization, trigger apoptosis in target cells by recruiting and activating intracellular death domains, leading to caspase cascade activation. TRAIL receptors are widely expressed, but their apoptotic response is preferentially selective for tumor cells, making them attractive therapeutic targets for cancer treatment. Besides inducing apoptosis, TRAIL receptors also modulate non-apoptotic signals—such as proliferation and migration—depending on cellular context. Clinical targeting includes recombinant ligand therapies (such as dulanermin) and agonist antibodies, but challenges such as tumor resistance, decoy receptor interference, and pharmacokinetics limit efficacy. TRAIL pathway modulation is generally safer than other TNF-ligand targeting due to lower toxicity in normal tissues. TRAIL and its receptors are under investigation as biomarkers and direct therapeutic targets for cancer and select inflammatory/fibrotic diseases

Other names

TRAIL receptorDeath Receptor 4 (DR4; TRAIL-R1)Death Receptor 5 (DR5; TRAIL-R2)KILLER/DR5TRICKKillerDecoy Receptor 1 (DcR1; TRAIL-R3)Decoy Receptor 2 (DcR2; TRAIL-R4)Osteoprotegerin (OPG; soluble decoy receptor)

Direct induction of apoptosis upon receptor agonism or ligand binding; Sensitization to chemotherapy or radiotherapy; Immune modulation (promotion of immunosurveillance, upregulation by immune cells); Selective activation of death domains in tumor cells; Activation or inhibition of downstream NF-κB or non-apoptotic pathways