Dysregulation of the Hippo pathway enhances PD-L2 transcription to promote cancer immune evasion

Abstract The Hippo pathway and its downstream effectors, YAP/TAZ, exhibit aberrant regulation across various cancer types, including head and neck squamous cell carcinoma, facilitating cancer cell growth. However, YAP/TAZ influence 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 high TMB and PD-L2 expression. YAP/TAZ hyperactivation induces loss of differentiation and genome instability, resulting in high TMB. YAP/TAZ recruits TEAD, BRD4, and RNA polymerase Ⅱ to the super-enhancer and promoter regions of PD-L1 and PD-L2. YAP/TAZ predominantly induce PD-L2, in turn, PD-L2 activates Stat3 that partially induces PD-L1 expression. YAP/TAZ recruit CD8+ T cells via TMB but evade them through PD-L2. YAP/TAZ hyperactivation may represent a better predictor for stratifying patients undergoing ICI therapy. Targeting YAP/TAZ/TEAD could offer a promising treatment avenue for cancers harboring YAP/TAZ hyperactivation.