The HDAC Inhibitor Domatinostat Promotes Cell-Cycle Arrest, Induces Apoptosis, and Increases Immunogenicity of Merkel Cell Carcinoma Cells

significant responses to immune checkpoint inhibitors. However, many patients experience primary or secondary resistance to these treatments, limiting their effectiveness. One way MCC evades the immune system is by reducing the expression of major histocompatibility complex I (MHC I) on its surface, making it less recognizable to T cells. Histone deacetylase inhibitors have been found to epigenetically reverse this downregulation by restoring the function of the antigen-processing machinery. Domatinostat, an orally available small-molecule inhibitor that targets histone deacetylase class I, is currently being evaluated in clinical trials as a way to overcome resistance to immunotherapy. In this study, we present preclinical data demonstrating domatinostat’s efficacy and mechanism of action in MCC. Single-cell RNA sequencing identified a specific gene expression profile related to antigen processing and presentation, cell-cycle arrest, and apoptosis following treatment. Functional assays confirmed that domatinostat induced G2M arrest and apoptosis. In surviving cells, the transcription and translation of genes involved in the antigen-processing machinery were upregulated, leading to increased MHC I surface expression. Overall, domatinostat not only has direct antitumoral effects but also restores HLA class I surface expression on MCC cells, making them more susceptible to recognition and elimination by cytotoxic T cells.