Vascular normalization by erianin unleashes CAR-T immunotherapy in glioblastoma

Abstract

Aberrant tumor vasculature is a major barrier limiting the efficacy of immunotherapy, including chimeric antigen receptor T-cell (CAR-T) therapy in solid tumors, by restricting T cell infiltration and impairing their functional activity. Glioblastoma (GBM), one of the most vascularized and immunotherapy-refractory cancers, exemplifies these challenges with its highly abnormal vessels and profoundly immune-cold microenvironment. Single-cell transcriptomic analysis of GBM samples suggests that endothelial-to-mesenchymal transformation (Endo-MT) is a key mechanism contributing to vascular abnormalities. Here, we conduct functional screening using a curated chemical library and identify erianin, a natural small-molecule compound, as a potent inhibitor of Endo-MT, thereby normalizing tumor vasculature and subsequently enhancing T cell infiltration in GBM mouse models. Importantly, erianin sensitizes GBM to Egfrviii CAR-T cell therapy and improves chemotherapy efficacy in preclinical models. Chemoproteomic and biophysical analyses reveal that erianin targets P4HA1 at the Arg379 site within the α-ketoglutarate (α-KG) binding pocket, leading to downregulation of the HIF1α/SNAIL/SLUG pathway, thereby restoring endothelial integrity by stabilizing VE-cadherin-mediated junctions and upregulating ICAM1 to enhance T-cell adhesion. These findings highlight erianin’s potential to overcome vascular barriers and reprogram the tumor microenvironment, providing a novel therapeutic strategy to enhance immunotherapy in GBM and other solid tumors.