CASP8 and cancer: While additional work will be required to fully understand why TRAIL engages apoptosis preferentially through TRAIL-R1, or how TRAIL-R1 engages the caspase-8 machinery in the absence of TRAIL during unresolved UPR, our findings provide novel insights to TRAIL agonist receptors physiological function and delineate TRAIL-R1 as a priority for cancer therapy.