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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.
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.
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).
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