{"entity":{"id":"extrinsic-apoptosis-death-receptors","kind":"pathway","name":"Extrinsic apoptosis (death receptors)","aka":[],"tldr":"Immune cells kill by touch: they present FAS ligand or TRAIL to a target cell, whose death receptors then trigger self-destruction from the outside in. Tumours cut this wire by deleting the receptors or over-producing decoys and blockers.","summary":"FASL, TRAIL and TNF bind death receptors (FAS, DR4/DR5, TNFR1), recruiting FADD and pro-caspase-8 into the DISC; active caspase-8 cleaves caspase-3/7 directly (type I cells) or cleaves BID to tBID to engage the mitochondrial pathway (type II). c-FLIP competes with caspase-8; XIAP restrains caspase-3/9; decoy receptors (DcR1-3) soak up ligand. Cytotoxic T and NK cells also deliver granzyme B through perforin pores, cleaving BID and caspases independently of receptors. Tumours lose FAS or CASP8 (head and neck, HPV-negative), overexpress c-FLIP and XIAP, and express FASL to kill infiltrating lymphocytes ('counterattack'). TRAIL agonists were safe but inactive; SMAC mimetics (IAP antagonists) and second-generation DR5 agonists are in trials; caspase-8 loss also switches death toward necroptosis.","asOf":"2026-09-09","wikipedia":"https://en.wikipedia.org/wiki/Death_receptor","links":[{"label":"Ashkenazi, Targeting the extrinsic apoptotic pathway in cancer (J Clin Invest 2015)","url":"https://doi.org/10.1172/JCI80420"}],"tags":["mechanism","mechanics-atlas"],"related":[],"cancers":[],"sections":[],"technologies":["car-t","t-cell-engager","checkpoint-inhibitor","bh3-profiling"],"targets":["bcl2","cd3","pd1"],"drugs":["venetoclax"],"companies":[],"institutions":[],"pathways":["apoptosis-bcl2","pd1-checkpoint","nk-cell-recognition"],"terms":["immunogenic-cell-death","adcc"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-ashkenazi-j-clin-invest"],"journals":[],"dependsOn":[],"notes":[],"analogy":"A doorbell wired to a self-destruct switch: immune cells ring it. Some tumours rip out the doorbell (FAS loss), some stuff the wiring with insulation (c-FLIP), and some install a second doorbell that rings nowhere (decoy receptors).","nodes":[{"id":"ctl","label":"CTL / NK cell","x":15,"y":12,"targetId":"cd3"},{"id":"lig","label":"FASL, TRAIL","x":45,"y":12},{"id":"dr","label":"FAS, DR4/DR5","x":45,"y":38},{"id":"dec","label":"Decoy receptors, c-FLIP","x":82,"y":25},{"id":"disc","label":"DISC: FADD, caspase-8","x":45,"y":62},{"id":"gzm","label":"Perforin / granzyme B","x":15,"y":40},{"id":"bid","label":"tBID → mitochondria","x":82,"y":62,"targetId":"bcl2"},{"id":"iap","label":"XIAP (IAPs)","x":82,"y":88},{"id":"casp","label":"Caspase-3/7 → death","x":45,"y":88}],"edges":[{"from":"ctl","to":"lig","type":"activates"},{"from":"ctl","to":"gzm","type":"activates"},{"from":"lig","to":"dr","type":"activates"},{"from":"dec","to":"dr","type":"inhibits"},{"from":"dr","to":"disc","type":"activates"},{"from":"dec","to":"disc","type":"inhibits"},{"from":"disc","to":"casp","type":"activates"},{"from":"disc","to":"bid","type":"activates"},{"from":"bid","to":"casp","type":"activates"},{"from":"gzm","to":"casp","type":"activates"},{"from":"iap","to":"casp","type":"inhibits"}],"interventions":["Checkpoint inhibitors, engagers and CAR-T all ultimately act through this wire, so caspase-8 or FAS loss confers immune resistance","SMAC mimetics (IAP antagonists) lower the threshold; birinapant, xevinapant tested with chemoradiation","DR5 agonist antibodies and TRAIL-receptor engagers, largely inactive so far","BH3 mimetics engage the mitochondrial arm downstream of tBID"]},"route":"/pathways/extrinsic-apoptosis-death-receptors/","neighbours":{"technology":[{"id":"bh3-profiling","kind":"technology","name":"BH3 profiling (functional apoptosis testing)","route":"/technologies/bh3-profiling/"},{"id":"car-t","kind":"technology","name":"CAR-T cell therapy","route":"/technologies/car-t/"},{"id":"checkpoint-inhibitor","kind":"technology","name":"Immune checkpoint inhibitors","route":"/technologies/checkpoint-inhibitor/"},{"id":"t-cell-engager","kind":"technology","name":"T-cell engagers (bispecific)","route":"/technologies/t-cell-engager/"}],"target":[{"id":"bcl2","kind":"target","name":"BCL-2","route":"/targets/bcl2/"},{"id":"cd3","kind":"target","name":"CD3","route":"/targets/cd3/"},{"id":"fas","kind":"target","name":"FAS","route":"/targets/fas/"},{"id":"pd1","kind":"target","name":"PD-1","route":"/targets/pd1/"},{"id":"tnfrsf10b","kind":"target","name":"TNFRSF10B","route":"/targets/tnfrsf10b/"},{"id":"tnfsf10","kind":"target","name":"TNFSF10","route":"/targets/tnfsf10/"}],"drug":[{"id":"venetoclax","kind":"drug","name":"Venetoclax","route":"/drugs/venetoclax/"}],"pathway":[{"id":"complement-in-cancer","kind":"pathway","name":"Complement in cancer","route":"/pathways/complement-in-cancer/"},{"id":"apoptosis-bcl2","kind":"pathway","name":"Intrinsic apoptosis (BCL-2 family)","route":"/pathways/apoptosis-bcl2/"},{"id":"nk-cell-recognition","kind":"pathway","name":"NK-cell recognition: missing self & stress ligands","route":"/pathways/nk-cell-recognition/"},{"id":"pd1-checkpoint","kind":"pathway","name":"PD-1 / PD-L1 immune checkpoint & T-cell activation","route":"/pathways/pd1-checkpoint/"}],"term":[{"id":"adcc","kind":"term","name":"ADCC (antibody-dependent cellular cytotoxicity)","route":"/terms/adcc/"},{"id":"immunogenic-cell-death","kind":"term","name":"Immunogenic cell death","route":"/terms/immunogenic-cell-death/"}],"paper":[{"id":"paper-ashkenazi-j-clin-invest","kind":"paper","name":"Targeting the extrinsic apoptotic pathway in cancer: lessons learned and future directions","route":"/key-papers/paper-ashkenazi-j-clin-invest/"}]}}