肿瘤细胞治疗研究
英文原题：Delivery of CAR T Cells in a Magnesium-Functionated Hydrogel Boosts Peritoneal Metastasis Treatment.
Delivery of CAR T Cells in a Magnesium-Functionated Hydrogel Boosts Peritoneal Metastasis Treatment.
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嵌合抗原受体 (CAR) T 细胞因肿瘤微环境中的抑制因素而在实体瘤中疗效有限。在本研究中，我们将细胞外镁 (Mg2+) 确定为 CAR-T 活性的药理学可调节调节因子。补充 Mg2+ 增加了早期激活并增强了细胞毒性读出指标，包括 IFN-分泌和靶细胞裂解。为了定位这一线索，我们工程化了一种由 Mg2+ 离子交联的磷酸化透明质酸水凝胶 (HA-Mg Gel)，其形成原位富含 Mg2+ 的龛。在该龛中，CAR-T 细胞在肿瘤-T 细胞界面表现出增强的肌动蛋白聚合，并在体外显示出增强的激活和效应功能。在 Capan-2 腹膜转移模型中，腹腔注射 CAR-T@HA-Mg Gel 产生了持久的肿瘤控制，并与对照相比显著延长了生存期。这些发现将细胞外 Mg2+ 定位为 CAR-T 活性的调节因子，并提出了一种生物材料引导的非遗传策略，以改善实体瘤的 CAR-T 细胞治疗。
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- 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.
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