Our newly designed high‐potency and HDAC1/2/6 selective inhibitor, SDFZ‐8, specifically upregulated PD‐L1 expression and downregulated PD‐1 expression in tumor‐infiltrating and spleen immune cells, suggesting its potential to enhance the efficacy of anti‐PD‐L1 blockade without promoting immunosuppression effects mediated by PD‐1/PD‐L1 signaling. Here, HDAC1 is linked to neoplasm.