Circulating immune cells that have interacted with tumor tissue exhibit distinct characteristics compared to those in healthy individuals, providing potential biomarkers for tumor presence and malignancy. However, the epigenetic mechanisms governing these immune cells, particularly chromatin accessibility, remain poorly understood in cancer. In this study, we investigated chromatin accessibility and transcription factor binding in peripheral blood mononuclear cells from dogs with mammary gland tumors using ATAC-seq. Our analysis revealed significant changes in chromatin accessibility near genes associated with immune function, neuronal activity, and lipid metabolism. Notably, we identified CEBPD-bound peaks that were upregulated in PBMCs from tumor-bearing dogs and demonstrated that the transcription of their associated genes, CD47 and MAP4K4, was also elevated in monocytes under cancer co-culture conditions. This effect was mitigated following CRISPR interference of these regulatory regions. These findings highlight the crucial role of chromatin accessibility in shaping the immune response to cancer and suggest potential therapeutic targets for immune modulation.