VPS37A loss creates CASP8-dependent vulnerability via the MAP3K7-NF-κB-CFLAR axis.

VPS37A, a subunit of ESCRT-I involved in endosomal sorting and autophagy, is frequently downregulated in diverse human cancers. In this study, we showed that VPS37A downregulation, as part of a large chromosome 8p deletion, arises early during tumorigenesis and persists throughout tumor progression. Integrative analysis of VPS37A gene copy number and CRISPR dependency revealed that VPS37A deficiency creates a synthetic lethal dependency on the MAP3K7-NF-κB-CFLAR axis, and targeting this axis triggered CASP8-mediated apoptosis and suppressed tumor growth. This synthetic vulnerability depends on ATG8ylated membranes, which serve as a platform for CASP8 activation upon inhibition of phagophore closure, and can be triggered without disrupting receptor sorting. Consistently, despite frequent co-deletion of VPS37A and the death receptors TNFRSF10A/B, inhibition of the MAP3K7-NF-κB-CFLAR axis selectively induced apoptosis in spheroid tumors with 8p deletion. These results uncover a selective vulnerability in cancer cells harboring VPS37A/8p loss, providing a mechanistic rationale for targeted therapeutic intervention.