Xiaoyu Feng,1,* Hao Zhu,2,* Jingwen Shen,1 Yan Wang,1 Shutong Liu,1 Xinjie Chen,1 Yaohua Ke,1 Dinghu Zhang,3 Lixia Yu,1 Baorui Liu,1 Qin Liu,1 Hao Wang,4 Yanhong Chu1 

1Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, People’s Republic of China; 2Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, People’s Republic of China; 3Department of Interventional Radiology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, People’s Republic of China; 4Department of Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Yanhong Chu, Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, People’s Republic of China, Email chu950518@163.com Hao Wang, Department of Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, People’s Republic of China, Email wanghaosurg@126.com

Introduction: 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 (ZnO2), and manganese peroxide (MnO2) to alleviate hypoxia and enhance dendritic cell (DC)-mediated antitumor immunity.
Methods: 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.
Results: The oxygen-generating MSN formulation effectively alleviated intratumoral hypoxia, promoted DC maturation (CD80+CD86+), 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.
Conclusion: 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.
Plain Language Summary: Adoptive T cell therapy is a promising treatment that uses a person’s own immune cells to fight cancer. However, it does not work well in solid tumors because the tumor environment is often low in oxygen and blocks immune responses. To solve this problem, our research team developed tiny particles, called MSN-R837-MnO2/ZnO2 nanoparticles, that are specially designed to help immune cells work better in tumors. These nanoparticles respond to the acidic conditions found in solid tumors. Once they arrive at the tumor site, they do several important things:They release oxygen to improve the low-oxygen conditions (called hypoxia) inside the tumor.They activate immune cells called dendritic cells (DCs), which help trigger stronger immune attacks.
They support the activity of adoptive T cells, which are the key cancer-fighting cells used in this therapy.In tests on mice with liver tumors, we found that these nanoparticles reduced tumor growth, improved oxygen levels in the tumor, and helped immune cells enter and stay active inside the tumor. Mice treated with our approach lived longer and had fewer side effects. This study shows that carefully designed nanoparticles can create a more supportive environment for immune cells in solid tumors. Our work could help make adoptive T cell therapy more effective and safer for people with difficult-to-treat cancers in the future.

Keywords: adoptive T cell therapy, hypoxia, nanoparticles, tumor microenvironment