Dual Histone Deacetylase/PD-1/PD-L1 Inhibitors Reprogram Tumor−Immune Interactions and Are Effective in Therapy-Resistant Melanoma
Alessia Raucci, Alessandra Fragale, Ilenia Pacella, Sabrina Garbo, Carola Castiello, Chiara Lambona, Alessandra Pinzon Grimaldos, Tommaso Priamo, Tiziano Giacomelli, Clemens Zwergel, Francesco Fiorentino, Rossella Fioravanti, Silvio Aprile, Nicoletta Antonini, Laura Lattanzi, Giulia Romagnoli, Simona Donati, Maria Buoncervello, Felicia Grasso, Enkeleta Berisha, Cecilia Battistelli, Silvia Piconese, Lucia Gabriele, Sergio Valente, Antonello MaiAbstract
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.