Dysregulation of the Hippo pathway enhances PD-L2 transcription to promote immune evasion in head and neck squamous cell carcinoma.

The Hippo pathway and its downstream effectors, YAP/TAZ, exhibit aberrant regulation in head and neck squamous cell carcinoma, facilitating cancer cell growth. However, the influence of YAP/TAZ on cancer immune evasion remains poorly understood. Herein, we show that cancer patients harboring mutations regulating the Hippo pathway and YAP/TAZ hyperactivation may be sensitized to immune checkpoint inhibitor (ICI) therapy owing to genome instability and PD-L2 expression. LATS1/2 deletion, accompanied by YAP/TAZ hyperactivation, was associated with loss of squamous differentiation and genome instability, which may contribute to elevated DNA damage. Our data suggest that YAP/TAZ may recruit TEAD, BRD4, and RNA polymerase Ⅱ to the super-enhancer and promoter regions of PD-L1 and PD-L2. YAP/TAZ predominantly contribute to PD-L2 expression, which is associated with Stat3 activation, partially enhancing PD-L1 transcription. YAP/TAZ-activated cells can be targeted by antigen-specific T cells but evade them through PD-L2. These findings suggest that Hippo pathway alterations and associated YAP/TAZ hyperactivation may serve as potential prognostic factors for stratifying patients undergoing ICI therapy. Targeting YAP/TAZ/TEAD could offer a promising treatment avenue for cancers harboring YAP/TAZ hyperactivation.