A Tetramethylpyrazine Releasing Hydrogel can Potentiate CAR-T Cell Therapy against Triple Negative Breast Cancer by Reprogramming Tumor Vasculatures

Irregular vasculature of solid tumors has proven to be a pivotal factor restricting their response to chimeric antigen receptor-T (CAR-T) cell therapy because it is tightly associated with hypoxia and other biological barriers. Herein, an injectable hydrogel composed of poly (ethylene glycol) dimethacrylate (PEGDMA) and ferrous chloride (FeCl2) responding to endogenous hydrogen peroxides (H2O2) is developed to enable sustained intratumoral release of Chinese herbal extracts tetramethylpyrazine (TMP). TMP is selected due to its potency in activating vascular endothelial growth factor (VEGF) expression and the endothelial nitric oxide synthase/nitric oxide (eNOS/NO) axis inside vascular endothelial cells. Upon being fixed inside tumors with the PEGDMA based hydrogel, TMP can remodel tumor vasculature by simultaneously promoting angiogenesis and dilating tumor vasculature and thus attenuate tumor hypoxia in two murine xenografts bearing human triple negative breast cancer (TNBC). Resultantly, treatment with TMP fixation potentiates the tumor suppression effect of intravenously injected epidermal growth factor receptor expressing CAR-T (HER-1-CAR-T) cells toward two TNBC tumor xenografts by promoting their tumor infiltration, survival, and effector function. This study highlights a concise yet effective approach to reinforce the therapeutic potency of CAR-T cells towards targeted solid tumors by simply remodeling tumor vasculature.