Unlocking the Therapeutic Potential of HDAC Inhibitors in Colorectal Cancer: Mechanisms, Efficacy, and Future Perspectives.

Colorectal cancer (CRC) is a predominant malignancy of the digestive tract globally, with primary treatment strategies including surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy. Recently, histone deacetylases (HDACs) and their inhibitors (HDACi) have emerged as promising therapeutic targets in CRC. As critical epigenetic regulators, HDACs influence gene expression and cellular processes, thereby affecting tumor initiation, progression, and immune evasion. Growing evidence suggests that HDAC inhibitors not only induce apoptosis and suppress cell proliferation but also potentiate the effectiveness of immune checkpoint inhibitors (ICIs) and counteract drug resistance. This review summarizes the classification and functional mechanisms of HDACs in CRC, evaluates the clinical advancement of HDAC inhibitors as monotherapies and combination therapies (e.g., with chemotherapy or ICIs), and highlights innovations in HDAC inhibitors, such as PROTAC-based degraders and nanomaterial-mediated delivery systems. These developments provide valuable insights for the precision treatment of CRC.