An ultrasound-activated nanoplatform remodels tumor microenvironment through diverse cell death induction for improved immunotherapy

• Published in: Journal of controlled release Vol. 370; pp. 501 - 515
• Main Authors: Ma, Jingbo, Yuan, Haitao, Zhang, Jingjing, Sun, Xin, Yi, Letai, Li, Weihua, Li, Zhifen, Fu, Chunjin, Zheng, Liuhai, Xu, Xiaolong, Wang, Xiaoxian, Wang, Fujing, Yin, Da, Yuan, Jimin, Xu, Chengchao, Li, Zhijie, Peng, Xin, Wang, Jigang
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.06.2024
• Subjects: antibodies; apoptosis; cancer therapy; cold; Ferroptosis; Immunogenic cell death; immunogenicity; immunosuppression; immunotherapy; nanocomposites; nanomedicine; neoplasms; reactive oxygen species; Sonodynamic therapy; Synergistic therapy; T-lymphocytes; tannins; Tumor microenvironment; ultrasonic treatment; Ferroptosis; Tumor microenvironment; Sonodynamic therapy; Immunogenic cell death; Synergistic therapy
• ISSN: 0168-3659; 1873-4995; 1873-4995
• DOI: 10.1016/j.jconrel.2024.05.001

Although nanomaterial-based nanomedicine provides many powerful tools to treat cancer, most focus on the “immunosilent” apoptosis process. In contrast, ferroptosis and immunogenic cell death, two non-apoptotic forms of programmed cell death (PCD), have been shown to enhance or alter the activity of the immune system. Therefore, there is a need to design and develop nanoplatforms that can induce multiple modes of cell death other than apoptosis to stimulate antitumor immunity and remodel the immunosuppressive tumor microenvironment for cancer therapy. In this study, a new type of multifunctional nanocomposite mainly consisting of HMME, Fe3+ and Tannic acid, denoted HFT NPs, was designed and synthesized to induce multiple modes of cell death and prime the tumor microenvironment (TME). The HFT NPs consolidate two functions into one nano-system: HMME as a sonosensitizer for the generation of reactive oxygen species (ROS) 1O2 upon ultrasound irradiation, and Fe3+ as a GSH scavenger for the induction of ferroptosis and the production of ROS ·OH through inorganic catalytic reactions. The administration of HFT NPs and subsequent ultrasound treatment caused cell death through the consumption of GSH, the generation of ROS, ultimately inducing apoptosis, ferroptosis, and immunogenic cell death (ICD). More importantly, the combination of HFT NPs and ultrasound irradiation could reshape the TME and recruit more T cell infiltration, and its combination with immune checkpoint blockade anti-PD-1 antibody could eradicate tumors with low immunogenicity and a cold TME. This new nano-system integrates sonodynamic and chemodynamic properties to achieve outstanding therapeutic outcomes when combined with immunotherapy. Collectively, this study demonstrates that it is possible to potentiate cancer immunotherapy through the rational and innovative design of relatively simple materials. Herein, we developed a novel nanoplatform capable of inducing various modes of cell death to stimulate antitumor immunity and remodel the immunosuppressive tumor microenvironment. Briefly, we designed and synthesized a new type of multifunctional nanoplatform, HFT NPs, which consolidate two functions into one nano-system: HMME as a sonosensitizer for the generation of reactive oxygen species (ROS) 1O2 upon ultrasound irradiation and Fe3+ as a GSH scavenger for the induction of ferroptosis and the production of ROS (·OH) through inorganic catalytic reaction. The data from in vitro and in vivo studies demonstrate that the HFT NPs administration and local ultrasound irradiation induce the occurrence of apoptosis, ferroptosis, and immunogenic cell death (ICD), and inhibit tumor growth in vivo. Notably, the combination of HFT NP treatment with immune checkpoint inhibitors, such as anti-PD-1 antibody, resulted in remarkable anticancer activity, effectively halting tumor growth. [Display omitted]