HDAC inhibitors in cancer therapy: sensitization mechanisms, combination strategies, and translational challenges

Histone deacetylases (HDACs) are key regulators of chromatin architecture and gene expression, and their dysregulation is closely linked to tumorigenesis, making them attractive targets for cancer therapy. Histone deacetylase inhibitors (HDACis) exert broad antitumor effects by modulating both epigenetic and non-epigenetic pathways. Although HDACis have demonstrated clinical activity in selected hematologic malignancies, their limited efficacy as monotherapy and limited therapeutic benefit in many solid tumors continue to constrain their broader clinical utilization. Accumulating evidence suggests that HDACis may have greater clinical value as treatment sensitizers and synergistic partners in combination regimens. Across chemotherapy, radiotherapy, targeted therapy, endocrine therapy, and immunotherapy, they enhance therapeutic responses through a range of interconnected mechanisms, including chromatin relaxation, impairment of DNA damage repair, induction of apoptosis, suppression of cell cycle progression, inhibition of oncogenic signaling pathways, and remodeling of the immune microenvironment. In this review, we outline the classification and biological functions of HDACs, along with an overview of representative HDACis. We focus on the synergistic and sensitizing roles these agents play across major anticancer modalities and discuss the molecular mechanisms underlying their therapeutic effects. We further discuss key translational barriers, including insufficient isoform selectivity, off-target toxicity, tumor heterogeneity, and inefficient drug delivery. Finally, we highlight emerging strategies-including isoform-selective inhibitors, mechanism-based biomarkers, rationally designed combinations, targeted delivery platforms, and dual- or multi-target agents. Overall, this review provides a comprehensive overview of HDACi-based combination therapies and their therapeutic and translational implications.