Dual Histone Deacetylase/PD-1/PD-L1 Inhibitors Reprogram Tumor−Immune Interactions and Are Effective in Therapy-Resistant Melanoma

Epigenetic modulators and immune checkpoint inhibitors represent two major therapeutic avenues in oncology, yet resistance and recurrence limit their efficacy. To address this, we designed and synthesized a series of dual histone deacetylase (HDAC)/PD-1/PD-L1 inhibitors (compounds 1−6). Among them, compounds 4 (HDAC6-selective) and 5 (HDAC1−3-selective) emerged as the most promising, both disrupting the PD-1/PD-L1 interaction in the nanomolar range and reducing tumor cell viability in vitro. Compound 4 counteracted T cell exhaustion, reshaped the immune landscape in vivo by enhancing neutrophil and NK cell activity, and showed potent antitumor activity in human BRAF-mutated melanoma models, including vemurafenib-resistant cells. Compound 5 exhibited strong direct cytotoxicity and induced PD-L1 expression, highlighting complex checkpoint regulation. Collectively, these findings support dual HDAC/PD-1/PD-L1 inhibition as a strategy to reprogram tumor−immune interactions and overcome resistance, with differential isoform selectivity proving critical for translational optimization.