# Extrinsic apoptosis (death receptors)

Source: https://onco.cc/pathways/extrinsic-apoptosis-death-receptors/  
OnCo record `extrinsic-apoptosis-death-receptors` (Pathway). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Fields

- Kind: Pathway
- Last checked: 2026-09-09
- Tags: mechanism; mechanics-atlas
- 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).
- 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

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Death_receptor
- Ashkenazi, Targeting the extrinsic apoptotic pathway in cancer (J Clin Invest 2015): https://doi.org/10.1172/JCI80420

## Connected records

- technologies: [BH3 profiling (functional apoptosis testing)](https://onco.cc/technologies/bh3-profiling/), [CAR-T cell therapy](https://onco.cc/technologies/car-t/), [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/), [T-cell engagers (bispecific)](https://onco.cc/technologies/t-cell-engager/)
- targets: [BCL-2](https://onco.cc/targets/bcl2/), [CD3](https://onco.cc/targets/cd3/), [FAS](https://onco.cc/targets/fas/), [PD-1](https://onco.cc/targets/pd1/), [TNFRSF10B](https://onco.cc/targets/tnfrsf10b/), [TNFSF10](https://onco.cc/targets/tnfsf10/)
- drugs: [Venetoclax](https://onco.cc/drugs/venetoclax/)
- pathways: [Complement in cancer](https://onco.cc/pathways/complement-in-cancer/), [Intrinsic apoptosis (BCL-2 family)](https://onco.cc/pathways/apoptosis-bcl2/), [NK-cell recognition: missing self & stress ligands](https://onco.cc/pathways/nk-cell-recognition/), [PD-1 / PD-L1 immune checkpoint & T-cell activation](https://onco.cc/pathways/pd1-checkpoint/)
- terms: [ADCC (antibody-dependent cellular cytotoxicity)](https://onco.cc/terms/adcc/), [Immunogenic cell death](https://onco.cc/terms/immunogenic-cell-death/)
- key papers: [Targeting the extrinsic apoptotic pathway in cancer: lessons learned and future directions](https://onco.cc/key-papers/paper-ashkenazi-j-clin-invest/)

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