The Multifaceted Roles of the Hippo-Yes-Associated Protein (YAP)/Transcriptional Coactivator with a PDZ-Binding Motif Pathway in Regulating the Tumor Microenvironment.

Abstract

The Hippo-Yes-associated protein (YAP)/transcriptional coactivator with a PDZ-binding motif (TAZ) pathway is frequently dysregulated in cancers. Beyond tumor cell-intrinsic functions of this pathway, Hippo-YAP/TAZ signaling exerts profound influences on the tumor microenvironment (TME). In this work, we discuss recent advances in understanding how this pathway modulates the immune landscape, cancer-associated fibroblasts (CAFs), and tumor vasculature. We first examine its roles in shaping tumor immunity through regulation of the expression of cytokines, chemokines, and immune checkpoint molecules by tumor cells. We then outline how YAP/TAZ drives fibroblast activation, matrix stiffening, and promotes cancer-associated fibrosis. Finally, we highlight its reciprocal regulation with vascular endothelial growth factor (VEGF) and other proangiogenic factors that control endothelial proliferation and vessel remodeling. Together, these findings position the Hippo-YAP/TAZ axis as a key orchestrator of the immune, stromal, and vascular components of the tumor niche and a promising target for therapeutic intervention.