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, Fe 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) O upon ultrasound irradiation, and Fe 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.

中文翻译：

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超声激活纳米平台通过多种细胞死亡诱导重塑肿瘤微环境，以改善免疫治疗

尽管基于纳米材料的纳米医学提供了许多强大的癌症治疗工具，但大多数都关注“免疫沉默”的细胞凋亡过程。相比之下，铁死亡和免疫原性细胞死亡是程序性细胞死亡（PCD）的两种非凋亡形式，已被证明可以增强或改变免疫系统的活性。因此，需要设计和开发能够诱导细胞凋亡以外的多种细胞死亡模式的纳米平台，以刺激抗肿瘤免疫并重塑免疫抑制肿瘤微环境以用于癌症治疗。在这项研究中，设计并合成了一种主要由HMME、Fe和单宁酸组成的新型多功能纳米复合材料（称为HFT NPs），用于诱导多种细胞死亡模式并启动肿瘤微环境（TME）。 HFT NPs 将两种功能整合到一个纳米系统中：HMME 作为一种声敏剂，用于在超声波照射下产生活性氧 (ROS) O，而 Fe 作为 GSH 清除剂，用于诱导铁死亡并通过无机催化反应。 HFT NP 的施用和随后的超声处理通过消耗 GSH 和产生 ROS 导致细胞死亡，最终诱导细胞凋亡、铁死亡和免疫原性细胞死亡 (ICD)。更重要的是，HFT NPs和超声照射的结合可以重塑TME并招募更多的T细胞浸润，其与免疫检查点阻断抗PD-1抗体的结合可以根除免疫原性低和冷TME的肿瘤。这种新的纳米系统集成了声动力学和化学动力学特性，与免疫疗法相结合可实现出色的治疗效果。总的来说，这项研究表明，通过相对简单的材料的合理和创新设计，可以增强癌症免疫疗法。