Vascular Normalization Augments the Antitumor Efficacy of Combined HDAC Inhibitor with Immunotherapy in Solid Tumors

Abstract Immunotherapy has made remarkable strides in the treatment of solid tumors, but its efficacy as a single agent in immunologically cold tumors remains limited. Therefore, it is necessary to explore novel drug combinations to further optimize immunotherapy. Herein, we demonstrated that the histone deacetylase inhibitor (HDACi) chidamide enhanced chromatin accessibility at the promoters of genes that encode effector molecules in CD8+ T cells, thereby augmenting their antitumor capabilities. However, HDACi also induced the expression of VEGFA in protumorigenic macrophages, which led to vascular abnormalization and hindered immune cell infiltration, compromising its potential synergistic effect with immunotherapy. Accordingly, combining antiangiogenic therapy counteracted the angiogenic effects of HDACi, collaboratively unleashing the infiltration and functionality of cytotoxic CD8+ T cells. These findings were confirmed by single-cell RNA sequencing data from our patient samples. Thus, through mechanistic research, we propose a new therapeutic approach by the combination of HDACi, antiangiogenic therapy, and immunotherapy, highlighting its potential application across diverse solid tumors. Significance: The challenges of tumor therapy primarily lie in developing novel intervention strategies to shift the tumor microenvironment toward an antitumor phenotype. Herein, we discovered that the combination of HDACi and antiangiogenic therapy promoted the functionality and infiltration of CD8+ T cells, ultimately remodeling the tumor microenvironment and boosting immunotherapy efficacy.