Epigenetic Activation of YAP by SETD8 Orchestrates Tumorigenesis and Immune Suppression

Epigenetic dysregulation is a hallmark of cancer and epigenetic therapies offer promising avenues to combat malignancies. The Hippo-YAP pathway, a key regulator of proliferation, apoptosis, and cell fate, drives tumor growth, metastasis, and immune evasion yet remains difficult to target directly. Using liver cancer as a model, we identify the histone methyltransferase SETD8 as a critical mediator of YAP-driven hepatomegaly and tumorigenesis in vivo with minimal impact on normal liver homeostasis. Beyond tumor intrinsic effects, SETD8 inhibition reshaped the tumor microenvironment by reducing PMN-MDSC and M2 macrophage infiltration and enhancing T cell activation. Mechanistically, YAP recruits SETD8 to its target loci to promote H4K20 mono-methylation, thereby increasing chromatin accessibility and amplifying transcriptional output. Pharmacological inhibition of SETD8 suppressed YAP-driven tumor growth, induced senescence, and restored cytotoxic T cell responses. Importantly, SETD8 blockade synergized with immune checkpoint inhibitors to further restrain tumor growth and enhance antitumor immunity. Patient derived liver tumor organoids, which closely recapitulate clinical tumors, displayed markedly higher sensitivity to SETD8 inhibition than normal liver organoids. Together, these findings establish SETD8 as a central regulator of YAP mediated oncogenic and immunosuppressive programs and highlight SETD8 targeted therapy, alone or combined with immunotherapy, as a promising strategy for malignancies.