Preclinical Characterization of SDFZ‐8, a Highly Potent HDAC1 Inhibitor, for Cancer Immunotherapy

ABSTRACT The histone deacetylases (HDACs) family plays a critical role in tumorigenesis and has been identified as having a significant impact on tumor immunity. Herein, we employed a fragment‐centric structure‐based design platform, leading to the discovery of SDFZ‐8 as a highly potent HDAC1 inhibitor (IC 50 = 0.4 nM). SDFZ‐8 exhibits strong antiproliferative effects by enabling histone acetylation and inducing cell apoptosis. Crucially, SDFZ‐8 treatment led to a significant enhancement of antitumor immunity, as evidenced by increased activation of T cells, enhanced polarization of M1‐type macrophages, improved antigen presentation, and alleviation of the immunosuppressive tumor microenvironment. Specifically, we observed that SDFZ‐8 notably upregulated the expression of PD‐L1 in both tumor cells and tumor‐infiltrating lymphocytes, which is closely associated with its inhibition against HDAC1. Of particular interest, combining SDFZ‐8 with PD‐L1 blockade resulted in a synergistic antitumor effect surpassing that of either monotherapy. Taken together, our findings establish SDFZ‐8 as a novel HDAC1 inhibitor that concurrently targets tumor cells and immune evasion mechanisms, providing a rational combinatorial strategy to enhance cancer immunotherapy efficacy.