YAP1 Is a Crucial Nexus in the Tumor Microenvironment

Yes-associated protein-1 (YAP1) is an oncogenic effector of the Hippo signaling pathway, activated in several cancer types, and has been extensively studied in cancer progression and therapy. A large number of studies have established the importance of YAP1 in promoting cell-autonomous functions, including uncontrolled growth, sustained proliferative signaling, drug resistance, and metastasis, across multiple cancer types. Therapeutic targeting of YAP1 to combat incurable neoplasms has been the focus of intense investigations. Solid tumors exhibit an organ-like morphology that comprises malignant cells, nonmalignant cells such as fibroblasts, endothelial cells, and immune cells, and non-cellular components, including the extracellular matrix and exosomal vesicles. Tumor progression is accompanied by persistent, reciprocal interactions between malignant cells and other cell types in the tumor microenvironment (TME). Ample evidence indicates the functional importance of YAP1 in nonmalignant components of the TME, which fuel cancer progression. In this review, we provide a comprehensive overview of the functional significance of YAP1 and its downstream signaling pathways across different compartments of the TME, which orchestrate cancer growth, stemness, drug resistance, and metastasis. In particular, this review focuses on understanding the mechanisms by which YAP1 drives distinct cell types in the TME, including cancer-associated fibroblasts (CAFs), immune cells, endothelial cells, and exosome-derived factors, to fuel tumor progression. Furthermore, we summarize the progress in the development of recent YAP1 inhibitors, their mechanisms of action in Hippo-YAP1-dependent cancers, and their combination benefits with existing treatment strategies.