Intercellular interaction licenses TNFα/IFNγ-induced cancer cell apoptosis through the NF2–YAP–TRAIL pathway

Abstract How intercellular contact shapes tumor sensitivity to inflammatory cytokines remains poorly understood. Here, we show that tumor necrosis factor α (TNFα) and interferon γ (IFNγ) synergistically trigger extrinsic apoptosis in a striking density-dependent manner across diverse cancer cell lines. High cell density activates the NF2–LATS1/2–YAP Hippo pathway, leading to YAP inactivation and relieving its repression of the death ligand TRAIL. Integrated CRISPR screening and RNA-seq identify TRAIL as the key density-licensed effector: TRAIL loss selectively abolishes high-density sensitivity, without affecting baseline killing at low density, whereas TRAIL restoration fully rescues it. In parallel, IFNγ amplifies TRAIL transcription via the STAT1–IRF1 axis, with IRF1 directly engaging the TRAIL promoter. Thus, TRAIL serves as an integration node that couples mechanical cues from cell–cell contact with immune cues from IFNγ to determine apoptotic responsiveness. Because NF2 loss and consequent YAP hyperactivation are common across many solid tumors, our findings suggest that disruption of the NF2–Hippo pathway may blunt cytokine-driven immune killing by limiting TRAIL induction. Accordingly, therapeutic YAP/TEAD inhibition or restoration of TRAIL signaling may enhance anti-tumor immune responses in NF2-deficient, YAP-hyperactive cancers.