肿瘤细胞治疗研究
英文原题：Sustained IL-15 release enhances CAR-T therapy in multiple myeloma via FOXO1 signaling axis activation.
Sustained IL-15 release enhances CAR-T therapy in multiple myeloma via FOXO1 signaling axis activation.
本研究开发了一种缺氧响应型N-803纳米凝胶（BiA-N-803 NG），用于控制释放IL-15超级激动剂，以增强CAR-T细胞治疗多发性骨髓瘤的疗效。
本研究开发了一种缺氧响应型N-803纳米凝胶（BiA-N-803 NG），用于控释IL-15超激动剂以增强多发性骨髓瘤中的CAR-T细胞治疗。该纳米凝胶双靶向CD138和TIM-3，并表现出稳定的缺氧触发释放特性。体外分析表明，BiA-N-803 NG促进CAR-T细胞扩增、记忆编程和抗肿瘤功能，其特征为记忆T细胞亚群增加和耗竭表型减少。转录组分析确定FOXO1信号轴的激活是CAR-T细胞记忆分化的关键机制。体内研究进一步显示CAR-T细胞持久性改善、NK细胞募集增强以及免疫抑制细胞浸润减少，共同导致多发性骨髓瘤中免疫微环境重塑和治疗耐久性提高。
This study developed a hypoxia-responsive N-803 nanogel (BiA-N-803 NG) for controlled release of an IL-15 superagonist to enhance CAR-T cell therapy in multiple myeloma. The nanogel was dual-targeted to CD138 and TIM-3 and exhibited stable, hypoxia-triggered release properties. In vitro analyses demonstrated that BiA-N-803 NG promoted CAR-T cell expansion, memory programming, and antitumor function, characterized by increased memory T-cell subsets and reduced exhaustion phenotypes. Transcriptomic profiling identified activation of the FOXO1 signaling axis as a key mechanism underlying CAR-T cell memory differentiation. In vivo studies further showed improved CAR-T cell persistence, enhanced NK cell recruitment, and reduced infiltration of immunosuppressive cells, collectively leading to a remodeled immune microenvironment and improved therapeutic durability in multiple myeloma.
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