Advances of HDAC inhibitors in tumor therapy: potential applications through immune modulation

Abstract

Histone deacetylase inhibitors (HDAC inhibitors, HDACi) have garnered considerable attention due to their potential in treating various types of malignant tumors. Histone deacetylases (HDACs) not only influence chromatin structure and gene transcription by regulating histone acetylation status but also acetylate various non-histone proteins. They are widely involved in several key biological processes, such as cell cycle regulation, apoptosis induction, and immune responses. HDACi exert their effects by inhibiting HDAC activity; however, these effects are highly concentration-dependent and non-selective. HDACi inevitably disrupt both gene expression and signaling networks, leading to multi-target, non-specific biological effects. This article focuses on the immunomodulatory mechanisms of HDACi, including their role in remodeling the tumor extracellular matrix and their impact on various immune cell populations. The synergistic potential of combining HDACi with other therapeutic approaches is also discussed. This review examines the application of HDACi across different tumor types, highlighting preclinical and clinical evidence that demonstrates the multifunctionality and efficacy of HDACi. By leveraging their unique mechanism of action, HDACi opens new avenues for enhancing antitumor immunity and achieving durable therapeutic responses. Future research and clinical trials will play a crucial role in optimizing the use of HDACi, elucidating resistance mechanisms, and identifying the most effective combinations to maximize patient benefit.

Keywords: HDACi; combination therapy; immunotherapy; tumor microenvironment; tumor therapy.

Figure 1

Dynamic regulatory processes of HDAC and HDACi. Chromatin consists of an association of DNA and proteins assembled in the nucleosome, the functional unit of genetic material. Nucleosomes are octamers composed of individual histone proteins. DNA is negatively charged, and histones are positively charged; therefore, the two are attracted to each other. Histone acetyltransferases(HATs) add an acetyl group to histone lysine residues. The positively charged acetyl group can neutralize the charge interaction between DNA and histones, thereby loosening the chromatin structure and facilitating transcription. In contrast, histone deacetylase removes the acetyl group from histones, reducing the degree of histone acetylation and inhibiting transcription. Inhibitors of histone deacetylase block the action of histone deacetylase, thereby increasing the degree of histone acetylation and loosening the chromatin structure, which promotes transcription.

Figure 2

Mechanism of action of HDACi on immune cells. ECM: HDACi promotes ECM reduction. Macrophage: HDACi promotes M1 macrophage polarization and inhibits M2 macrophage polarization. T cell: HDACi activates the Wnt/β-catenin signaling pathway, promotes cytokine release, and reduces the number of Tregs. B cell: HDACi promotes the reduction of autoreactive B cells, maintains the number of memory B cells, and promotes apoptosis of malignant B cells in B-cell lymphoma. NK cell, HDACi enhances cytotoxicity and promotes cell proliferation. DC, HDACi inhibits the release of cytokines by dendritic cells and suppresses their antigen-presenting capacity by downregulating the NF-κB signaling pathway.

Figure 3

Antitumor effects of HDACi. multiple myeloma: Multiple myeloma: CUDC-907 simultaneously targets HDAC and PI3K, reducing the expression of Bcl-xL and MCL-1, thereby inhibiting myeloma cell growth. Hodgkin lymphoma: Ixazomib combined with Belinostat can synergistically inhibit the NFE2L2 pathway, suppress proteasome activity, and thereby enhance cytotoxicity. Non-Hodgkin lymphoma: Volasertib combined with HDACi induces DNA damage, thereby inhibiting tumor growth. Lung cancer: 6a simultaneously targets HDAC and MIF, inducing histone acetylation and blocking the MIF-CXCR7-AKT pathway, thereby inhibiting the proliferation of NSCLC cells. Breast cancer: HDACi can promote metastasis by enhancing H3K9 acetylation of the NEDD9 gene promoter, upregulating NEDD9 expression, and activating FAK phosphorylation. FAK inhibitors can reverse this process. Pancreatic cancer: HDACi inhibits the SRF-FOXM1 transcriptional axis, downregulating the pro-fibrotic genes Acta2 and Col1a1 and the pro-inflammatory factor LIF, thereby inhibiting tumor growth. Colorectal cancer: HDACi reduces the phosphorylation level of Rb, preventing E2F1 from being released from the E2F1/Rb/HDAC1 complex. The retention of E2F1 prevents it from activating downstream target genes that drive the cell cycle process, ultimately inhibiting the growth of CRC cells. Cervical cancer, HDACi activates PINK1/Parkin-mediated mitochondrial autophagy, thereby inhibiting the growth of cervical cancer cells.