KAT5 is Dual-Function Therapeutic Target with Direct Antitumor and Immunomodulatory Activity in Endometrial Cancer.

Epigenetic dysregulation plays a vital role in the progression of endometrial cancer (EC), yet targeted treatment options remain limited. Here, we identified the histone acetyltransferase KAT5 as a therapeutic target in EC. KAT5 was significantly overexpressed in EC and correlated with poor patient outcome. Silencing KAT5 inhibited EC cell proliferation and tumor growth. KAT5-deficient EC cells exhibited impaired cytoskeletal dynamics, leading to heightened DNA damage and increased micronuclei formation. The release of micronuclear DNA into the cytoplasm activated the cGAS-STING pathway, thereby amplifying proinflammatory immune responses. Mechanistically, KAT5 acetylated H2A.Z to transcriptionally activate Arp2/3 complex genes, promoting actin polymerization and chromosomal stability. Inhibition of Arp2/3 or depletion of its subunit ARPC5 replicated the effects of KAT5 loss, whereas restoring ARPC5 mitigated chromosomal instability and cGAS activation. In transplantation models of EC cell lines and syngeneic murine Trp53-/-;Pten-/- EC organoids, pharmacological inhibition of KAT5 with NU9056 suppressed tumor progression and enhanced immune cell infiltration. NU9056 also induced Arp2/3 disruption, genomic instability, and cGAS-STING activation in patient-derived organoids from clinical endometrial cancer samples. Together, these findings highlight KAT5 as a promising therapeutic target in EC that influences chromatin remodeling, cytoskeletal dynamics, and immune modulation.