Epithelial cancer cells co-opt the death ligand TRAIL to avert extrinsic apoptosis while acquiring killing capacity.

Cancer cells avert apoptosis to sustain growth, evade immunity, and resist therapy. However, how they escape specific extrinsic death signals remains unclear. We show that certain epithelial carcinomas co-opt the death-receptor ligand Apo2L/TRAIL to suppress apoptosis while acquiring killing capacity. Analysis of CRISPR knockout screens from the Cancer Dependency Map uniquely identified TRAIL as an essential tumor necrosis factor superfamily member in epithelial malignancies. Renal cell carcinomas (RCC) and squamous cell carcinomas (SCC) expressed TRAIL within both malignant and nonmalignant compartments. In RCC, loss of the tumor suppressor VHL induced HIF2α-dependent TRAIL transcription, whereas in SCC, 3q26 amplification increased TRAIL abundance. Fractional TRAIL silencing revealed killing of TRAIL-deficient cells by TRAIL-expressing counterparts, while full silencing sensitized cells to extrinsic TRAIL. Mechanistically, endogenous TRAIL suppressed apoptosis through lysosomal degradation of its cognate death receptors. Thus, cancer cells can repurpose TRAIL via a surprising apoptotic "cloak-and-dagger" mechanism with significant therapeutic potential.