Targeting TEAD in cancers: paralog-specific biology, resistance and therapeutic opportunities

Abstract The TEA domain transcription factors TEAD1 to TEAD4 integrate Hippo signaling with transcriptional programs that govern tissue homeostasis and cancer progression. Their activity is shaped by cofactor engagement, palmitoylation, chromatin organization and extracellular cues, creating therapeutic vulnerabilities that vary with tumor lineage and cellular state. This review examines TEAD molecular architecture, physiological functions and paralog-specific biology, together with canonical regulation by NF2/Merlin and the Hippo kinase cascade and non-canonical inputs from mechanical cues, oncogenic signaling, metabolism and hypoxia. Particular attention is given to the distinct interactions of YAP1 and TAZ with TEAD and the contribution of alternative cofactors to transcriptional output. Across cancer types, the evidence distinguishes tumors with strong YAP1/TAZ-TEAD dependence, exemplified by NF2-deficient mesothelioma, from settings in which the pathway supports tumor plasticity, immune evasion and treatment resistance or may restrain tumor growth. These differences emphasize that TEAD expression or pathway activation alone does not establish functional dependence or reliably predict therapeutic response. Therapeutic approaches include TEAD lipid pocket inhibitors, disruptors of YAP1/TAZ-TEAD interactions, degraders, cofactor-switching compounds and YAP1-directed oligonucleotides. Early clinical findings with VT3989 in mesothelioma support the therapeutic potential of TEAD inhibition, while highlighting unresolved questions concerning patient selection, durability of benefit and renal tolerability. Priorities for clinical development include functional biomarkers of TEAD dependence, pharmacodynamic confirmation of target engagement and combinations guided by defined resistance mechanisms. Progress will depend on translating these mechanistic insights into durable antitumor efficacy at tolerable exposures in appropriately selected patients.