Advances in mechanisms, combined therapeutic strategies and dual-target inhibitors for synergistic antitumor effects of HDAC and PD-1/PD-L1 pathway.

Histone deacetylase (HDAC) inhibitors exert anti-tumor effects by modulating epigenetic states, cell cycle progression, and immune responses. This includes reactivating tumor suppressor genes, interfering with DNA damage repair processes, and enhancing anti-tumor immune responses. Programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors function by blocking the interaction between PD-1 and its ligand PD-L1, thereby restoring and augmenting T cell-mediated anti-tumor immunity. Studies have demonstrated that HDAC inhibitors can upregulate PD-L1 expression, potentially enhancing the efficacy of immune checkpoint inhibitors and improving therapeutic outcomes by modulating the tumor microenvironment. This review article systematically explores the mechanisms of interaction between HDAC and PD-1/PD-L1 in cancer therapy; recent advances in combination treatment strategies; and the current landscape of dual-target inhibitors from a drug design perspective. It provides a detailed discussion on the challenges and future directions associated with the combined application of HDAC inhibition and cancer immunotherapy, as well as the development of dual-function small molecules.