YAP1 signaling and cancer: molecular pathways reveal novel targeting opportunities

INTRODUCTION: The Hippo pathway plays a critical role in maintaining tissue homeostasis, regulating organ size, and controlling cellular processes. YAP1/TAZ activation drives oncogenesis, metastasis, and resistance to chemotherapy by promoting key cellular behaviors such as immune evasion and tumor cell survival. AREAS COVERED: This review synthesizes current advances in understanding how YAP1 and its paralog TAZ drive tumor initiation and progression. We highlight their central roles in sustaining cancer stem cell properties, promoting epithelial-to-mesenchymal transition, and shaping an immunosuppressive tumor microenvironment. Emerging therapeutic approaches targeting the YAP1/TAZ-TEAD transcriptional complex, including small-molecule disruptors of TEAD auto-palmitoylation, are evaluated alongside the challenges posed by pathway redundancy and context-dependent effects. EXPERT OPINION: Therapeutically inhibiting YAP1/TAZ signaling holds substantial promise. Yet the dual physiological roles of YAP1 in tissue repair and stemness underscore the need for highly selective and temporally controlled interventions. Rational combinations, such as pairing YAP1/TEAD inhibitors with immune checkpoint blockade, anti-fibrotic agents, may enhance clinical benefit. Future work should prioritize the development of robust biomarkers of YAP1 activation, deeper mapping of TEAD-dependent versus TEAD-independent functions, and optimization of strategies that maximize antitumor efficacy while limiting systemic toxicity.