Vascular Normalization Augments the Anti-tumor Efficacy of Combined HDAC Inhibitor with Immunotherapy in Solid Tumors

Abstract Immunotherapy has made remarkable strides in treatment of solid tumors, but its efficacy as a single agent in cold tumor remains limited. It is urgent to explore novel drug combinations to further optimize immunotherapy. Herein, we demonstrated the histone deacetylase inhibitor (HDACi), chidamide, enhanced chromatin accessibility at the promoters of effector molecules in CD8+ T cells, thereby augmenting their anti-tumor capabilities. Yet HDACi also induced the expression of VEGFa in pro-tumorigenic macrophages, which leaded to vascular abnormalization and hindered immune cells infiltration, compromising its potential synergistic effect with immunotherapy. Accordingly, combining anti-angiogenesis therapy counteracted the angiogenesis effects of HDACi, collaboratively unleashing the infiltration and functionality of cytotoxic CD8+ T cells. These findings were confirmed through scRNA-seq data from our patient samples. Thus, through mechanistic research, we proposed a new therapeutic approach by the combination of HDACi, anti-angiogenesis therapy, and immunotherapy and finally highlighted the potential application across diverse solid tumors.