The tumor microenvironment of colorectal cancer (CRC) exhibits a highly immunosuppressive phenotype, contributing to resistance against immunotherapy and poor prognosis in patients. Lysine acetyltransferase 6A (KAT6A) is significant in immune regulation and advanced breast cancer treatment. However, its mechanistic involvement in regulating anti-tumor immune responses in CRC remains unclear. Using clinical CRC cohorts, we evaluated KAT6A expression levels and their clinical significance in this study. We investigated its functional role through subcutaneous and metastatic tumor models in mice. Our findings demonstrate that KAT6A is overexpressed in CRC and correlates with poor prognosis. Mass cytometry (CyTOF) and ATAC-seq analyses revealed that KAT6A knockdown enhanced CD8 T cell infiltration by activating interferon (IFN) signaling pathways. Gene Set Enrichment Analysis (GSEA) and immunofluorescence assays confirmed that KAT6A knockdown activates the cGAS-STING pathway, subsequently inducing IFN-mediated immune responses. Mechanistically, knockdown of KAT6A relieves c-MYC/DNMT1-mediated repression of cGAS. We also evaluated the therapeutic effects of a KAT6A inhibitor alone and its combination with anti-PD-1 in microsatellite stable (MSS) and microsatellite instability-high (MSI-H) mouse models, demonstrating synergistic efficacy in combination therapy. Furthermore, in a cohort of CRC patients receiving immunotherapy, we showed that high KAT6A expression correlated with impaired treatment response, manifested by lower objective response rates, shorter progression-free survival (PFS), and decreased overall survival (OS). Importantly, this study reveals KAT6A's pivotal role in modulating CRC immune evasion via regulating endogenous IFN response of tumor cells, thereby establishing its potential as a therapeutic target for enhancing immunotherapy efficacy in CRC.