Feng Xiaoyu, Zhu Hao, Shen Jingwen, Wang Yan, Liu Shutong, Chen Xinjie, Ke Yaohua, Zhang Dinghu, Yu Lixia, Liu Baorui, Liu Qin, Wang Hao, Chu Yanhong
Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, People's Republic of China.
Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, People's Republic of China.
Int J Nanomedicine. 2025 Aug 20;20:10073-10087. doi: 10.2147/IJN.S522504. eCollection 2025.
Adoptive cell therapy (ACT) has emerged as a powerful strategy for eliciting tumor regression. However, its efficacy in solid tumors remains limited, primarily due to the immunosuppressive tumor microenvironment (TME). We developed a tumor microenvironment-responsive mesoporous silica nanosphere (MSN) formulation co-loaded with the immunostimulant imiquimod (R837), zinc peroxide (ZnO), and manganese peroxide (MnO) to alleviate hypoxia and enhance dendritic cell (DC)-mediated antitumor immunity.
The immunostimulatory efficacy of our nanoparticles was evaluated in vitro using DC activation assays and in vivo in an H22 murine hepatocellular carcinoma model. Flow cytometry was employed to assess immune cell populations in tumors and lymph nodes, while immunofluorescence microscopy was used to analyze tumor hypoxia and T cell infiltration.
The oxygen-generating MSN formulation effectively alleviated intratumoral hypoxia, promoted DC maturation (CD80CD86), and facilitated effector CD8 T cell infiltration into tumors. In vivo, co-administration of the nanoformulation with ACT led to enhanced tumor suppression and systemic antitumor immune responses without evident toxicity to major organs.
This oxygen-producing immunomodulatory nanoplatform remodels the immunosuppressive TME and significantly enhances the efficacy of ACT in solid tumors, offering a promising strategy for overcoming current barriers in T cell-based immunotherapy.
过继性细胞疗法（ACT）已成为一种引发肿瘤消退的有效策略。然而，其在实体瘤中的疗效仍然有限，主要原因是免疫抑制性肿瘤微环境（TME）。我们开发了一种肿瘤微环境响应性介孔二氧化硅纳米球（MSN）制剂，其共负载免疫刺激剂咪喹莫特（R837）、过氧化锌（ZnO）和过氧化锰（MnO），以缓解缺氧并增强树突状细胞（DC）介导的抗肿瘤免疫力。
我们使用DC激活试验在体外评估了纳米颗粒的免疫刺激功效，并在H22小鼠肝细胞癌模型中进行了体内评估。采用流式细胞术评估肿瘤和淋巴结中的免疫细胞群体，同时使用免疫荧光显微镜分析肿瘤缺氧和T细胞浸润情况。
产生氧气的MSN制剂有效缓解了肿瘤内缺氧，促进了DC成熟（CD80CD86），并促进效应性CD8 T细胞浸润到肿瘤中。在体内，纳米制剂与ACT联合给药导致增强的肿瘤抑制和全身抗肿瘤免疫反应，而对主要器官无明显毒性。
这种产生氧气的免疫调节纳米平台重塑了免疫抑制性TME，并显著提高了ACT在实体瘤中的疗效，为克服当前基于T细胞的免疫疗法中的障碍提供了一种有前景的策略。
