Deciphering the signaling landscape of YAP in the tumor microenvironment—Insights into hepatocellular carcinoma progression

Liver cancer stands as the sixth leading cause of cancer-related deaths globally, with hepatocellular carcinoma (HCC) being the most frequently diagnosed subtype. The hepatic tumor microenvironment (TME) comprises a complex array of cellular and non-cellular components, including activated hepatic stellate cells (HSCs), tumor-associated macrophages (TAM), endothelial cells, immune cells, and non-cellular elements such as growth factors, proteolytic enzymes, inhibitors, and extracellular matrix (ECM) proteins. The initiation and progression of HCC involve intricate interactions among hepatocytes, tumor cells, and non-tumor cells, including liver-resident non-parenchymal cells (NPCs). The Hippo-YAP pathway plays a crucial role in tumor development and initiation. YAP/TAZ, as primary effectors of the Hippo pathway, intricately connect with other signaling pathways relevant to tumors. YAP promotes the growth of cancer stem cells, the development of malignant phenotypes, and drug resistance, contributing significantly to cancer growth. This review focuses on the role of YAP in stromal cells as a mediator of HCC. We aim to present a comprehensive overview, not only consolidating existing knowledge but also paving the way for innovative exploration in pursuing effective therapeutic strategies against HCC.