HDAC3: A Multifaceted Modulator in Immunotherapy Sensitization.

Abstract

Histone deacetylase 3 (HDAC3) has emerged as a critical epigenetic regulator in tumor progression and immune modulation, positioning it as a promising target for enhancing cancer immunotherapy. This work comprehensively explores HDAC3's multifaceted roles, focusing on its regulation of key immune-modulatory pathways such as cGAS-STING, ferroptosis, and the Nrf2/HO-1 axis. These pathways are central to tumor immune evasion, antigen presentation, and immune cell activation. Additionally, the distinct effects of HDAC3 on various immune cell types-including its role in enhancing T cell activation, restoring NK cell cytotoxicity, promoting dendritic cell maturation, and modulating macrophage polarization-are thoroughly examined. These findings underscore HDAC3's capacity to reshape the tumor immune microenvironment, converting immunologically "cold tumors" into "hot tumors" and thereby increasing their responsiveness to immunotherapy. The therapeutic potential of HDAC3 inhibitors is highlighted, both as standalone agents and in combination with immune checkpoint inhibitors, to overcome resistance and improve treatment efficacy. Innovative strategies, such as the development of selective HDAC3 inhibitors, advanced nano-delivery systems, and integration with photodynamic or photothermal therapies, are proposed to enhance treatment precision and minimize toxicity. By addressing challenges such as toxicity, patient heterogeneity, and resistance mechanisms, this study provides a forward-looking perspective on the clinical application of HDAC3 inhibitors. It highlights its significant potential in personalized cancer immunotherapy, paving the way for more effective treatments and improved outcomes for cancer patients.