The multifaceted role of YAP in the tumor microenvironment and its therapeutic implications in cancer

The tumor microenvironment (TME) plays a critical role in cancer progression, immune evasion and therapeutic resistance. The transcriptional coactivators YAP and TAZ, key effectors of the Hippo signaling pathway, have emerged as central regulators of TME remodeling. YAP/TAZ are activated in both tumor and stromal compartments, where they function as mechanotransducers and integrate canonical Hippo pathway suppression, noncanonical microenvironmental cues and genetic or epigenetic signals to drive transcriptional programs. These changes collectively facilitate tumor immune evasion. YAP/TAZ further promote angiogenesis and upregulate PD-L1 expression in tumor cells and cancer-associated fibroblasts, and a subset of immunosuppressive cells in the TME, contributing to resistance to ICB. In addition to their tumor-intrinsic and stromal functions, YAP/TAZ impair antitumor immunity by altering immune cell differentiation and dampening effector responses. Targeting the YAP/TAZ-TEAD axis has shown potential efficacy when combined with immune checkpoint inhibitors, chimeric antigen receptor T cell therapies and tumor vaccines. Although challenges such as tumor selectivity and resistance mechanisms persist, advances in single-cell and spatial transcriptomics are enabling the dissection of YAP/TAZ-regulated networks and guiding the development of more precise therapeutic strategies. Collectively, YAP/TAZ inhibition offers a promising avenue to reprogram the TME and enhance the efficacy of next-generation cancer immunotherapies.