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

LATS1/2 deletion with YAP/TAZ hyperactivation in head and neck squamous cell carcinoma is linked to loss of squamous differentiation, genome instability, and increased PD-L2 expression.

• Why it matters: YAP/TAZ-driven immune evasion is poorly understood, limiting how Hippo pathway alterations could be used to predict or improve responses to immune checkpoint inhibitor therapy.
• What they did: The study analyzed cancer patients with Hippo pathway–regulating mutations and YAP/TAZ hyperactivation, and used mechanistic data suggesting YAP/TAZ recruit TEAD, BRD4, and RNA polymerase II to PD-L1/PD-L2 regulatory regions.
• The result: YAP/TAZ predominantly drive PD-L2 expression, which is associated with Stat3 activation and partially enhances PD-L1 transcription; YAP/TAZ-activated cells evade antigen-specific T cells via PD-L2, suggesting Hippo alterations may stratify ICI therapy.