Dysregulation of the Hippo pathway enhances PD-L2 transcription to promote immune evasion in head and neck squamous cell carcinoma
Abstract
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.
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BibTeX
@article{ando2026dysregulation,
title = {{Dysregulation of the Hippo pathway enhances PD-L2 transcription to promote immune evasion in head and neck squamous cell carcinoma}},
author = {Toshinori Ando and Kento Okamoto and Kuniaki Sato and Yusuke Goto and Hiroki Izumi and Nanako Kataoka and Yume Ueda and Yukina Kobayashi and Kai Omachi and Yuga Maeda and Hisako Furusho and Ramiro Iglesias-Bartolome and Tetsuya Yoshimoto and Tomoaki Shintani and Souichi Yanamoto and Mutsumi Miyauchi and J. Silvio Gutkind and Mikihito Kajiya},
journal = {Communications Biology},
year = {2026},
month = oct,
doi = {10.1038/s42003-026-11092-0},
url = {https://www.nature.com/articles/s42003-026-11092-0},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Dysregulation of the Hippo pathway enhances PD-L2 transcription to promote immune evasion in head and neck squamous cell carcinoma
AU - Toshinori Ando
AU - Kento Okamoto
AU - Kuniaki Sato
AU - Yusuke Goto
AU - Hiroki Izumi
AU - Nanako Kataoka
AU - Yume Ueda
AU - Yukina Kobayashi
AU - Kai Omachi
AU - Yuga Maeda
AU - Hisako Furusho
AU - Ramiro Iglesias-Bartolome
AU - Tetsuya Yoshimoto
AU - Tomoaki Shintani
AU - Souichi Yanamoto
AU - Mutsumi Miyauchi
AU - J. Silvio Gutkind
AU - Mikihito Kajiya
PY - 2026
DA - 2026/10/23
JO - Communications Biology
DO - 10.1038/s42003-026-11092-0
UR - https://www.nature.com/articles/s42003-026-11092-0
AB - 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.
SN - 2399-3642
ER -