Wang Baihui, Xue Yuchan, Jia Yang, Duan Yuyao, Li Dejun, Sui Minghao, Feng Yuemin, Wang Le, Ding Han, Wang Xinyu, Zhang Tianru, Sun Yanning, Liu Huimin, Qi Jianni, Duan Jiazhi, Zhao Songbo, Zhu Qiang
Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, P. R. China.
Department of Gastroenterology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, Shandong, 266001, P. R. China.
Small. 2025 Jun;21(25):e2501645. doi: 10.1002/smll.202501645. Epub 2025 May 9.
Chimeric antigen receptor (CAR)-T-cell therapy achieves considerable success in the treatment of malignant tumors, but clinical relapse due to the tumor microenvironment (TME) is very common. The TME of solid tumors is characterized by weak acidity, hypoxia, and elevated reactive oxygen species (ROS) levels, which collectively impair the function and persistence of infiltrating CAR-T cells. In this study, acid-sensitive responsive CaMnCO nanoparticles (CMC NPs), are developed that simultaneously mitigate TME acidosis and hypoxia. IL-21 is encapsulated within CMC NPs (denoted as CMC-21), which are then surface-conjugated to CAR-T cells as functional 'vitality backpacks' to enhance cellular activity. The CMC-21 backpack enables sustained release of IL-21, persistently enhancing CAR-T cell antitumor immunity across both low- and high-dose infusion regimens. Furthermore, CMC NPs exert dual modulatory effects on the TME by: 1) consuming protons to neutralize acidic conditions, and 2) catalytically converting endogenous HO to O to relieve hypoxia. This multimodal remodeling of the immunosuppressive TME significantly enhances the infiltration and activity of adoptively transferred CAR-T cells while simultaneously boosting endogenous T cell and NK cell recruitment in vivo. These findings establish a novel CAR-T cell enhancement strategy through sustained IL-21 release from CMC-21 backpacks, offering new possibilities for solid tumor immunotherapy.
嵌合抗原受体（CAR）-T细胞疗法在恶性肿瘤治疗中取得了显著成功，但由于肿瘤微环境（TME）导致的临床复发非常常见。实体瘤的TME具有弱酸性、缺氧和活性氧（ROS）水平升高的特点，这些因素共同损害浸润性CAR-T细胞的功能和持久性。在本研究中，开发了酸敏响应性CaMnCO纳米颗粒（CMC NPs），其可同时减轻TME酸中毒和缺氧。白细胞介素-21（IL-21）被封装在CMC NPs中（称为CMC-21），然后将其表面偶联到CAR-T细胞上作为功能性“活力背包”，以增强细胞活性。CMC-21背包能够持续释放IL-21，在低剂量和高剂量输注方案中持续增强CAR-T细胞的抗肿瘤免疫力。此外，CMC NPs对TME发挥双重调节作用：1）消耗质子以中和酸性条件，2）催化内源性HO转化为O以缓解缺氧。这种对免疫抑制性TME的多模式重塑显著增强了过继转移的CAR-T细胞的浸润和活性，同时在体内促进内源性T细胞和自然杀伤（NK）细胞的募集。这些发现通过CMC-21背包持续释放IL-21建立了一种新的CAR-T细胞增强策略，为实体瘤免疫治疗提供了新的可能性。
