The role of histone deacetylases (HDACs) in the tumor immune microenvironment of gynecologic tumors remains unexplored. We integrated data from The Cancer Genome Atlas and Human Protein Atlas to examine HDAC expression in breast, cervical, ovarian, and endometrial cancers. Elevated HDAC expression correlated with poor prognosis and highly malignant cancer subtypes. Gene Set Enrichment Analysis revealed positive associations between HDAC expression and tumor proliferation signature, while negative associations were found with tumor inflammation signature. Increased HDAC expression was linked to reduced infiltration of natural killer (NK), NKT, and CD8+ T cells, along with negative associations with the expression of PSMB10, NKG7, CCL5, CD27, HLA-DQA1, and HLA-DQB1. In a murine 4T1 breast cancer model, treatment with suberoylanilide hydroxamic acid (SAHA; HDAC inhibitor) and PD-1 antibody significantly inhibited tumor growth and infiltration of CD3+ and CD8+ T cells. Real-time polymerase chain reaction revealed upregulated expressions of Psmb10, Nkg7, Ccl5, Cd8a, Cxcr6, and Cxcl9 genes, while Ctnnb1 and Myc genes were inhibited, indicating tumor suppression and immune microenvironment activation. Our study revealed that HDACs play tumor-promoting and immunosuppressive roles in gynecologic cancers, suggesting HDAC inhibitors as potential therapeutic agents for these cancers.Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.