Delivery of CAR T Cells in a Magnesium-Functionated Hydrogel Boosts Peritoneal Metastasis Treatment

Abstract

Abstract Chimeric antigen receptor (CAR) T cells show limited efficacy in solid tumors due to suppressive factors in the tumor microenvironment. In this study, we identified extracellular magnesium (Mg2+) as a pharmacologically modulable regulator of CAR T activity. Mg2+ supplementation increased early activation and augmented cytotoxic readouts, including IFN-γ secretion and target-cell lysis. To localize this cue, we engineered a phosphorylated hyaluronic-acid hydrogel ionically cross-linked by Mg2+ (HA-Mg Gel), which forms an in situ Mg2+-rich niche. In this niche, CAR T cells exhibit reinforced actin polymerization at the tumor-T-cell interface and show enhanced activation and effector function in vitro. In a Capan-2 peritoneal metastasis model, intraperitoneal administration of CAR T@HA-Mg Gel produced durable tumor control and significantly prolonged survival compared with controls. These findings position extracellular Mg2+ as a modulator of CAR T activity and present a biomaterial-guided, nongenetic strategy to improve CAR T-cell therapy for solid tumors.