Myeloid-derived suppressor cells (MDSCs) play a crucial role in the immune escape mechanisms that limit the efficacy of immunotherapeutic strategies. In the tumor microenvironment, NLRP3 inflammasome-driven Interleukin-1β (IL-1β) production serves to dampen antitumor immune responses, promoting tumor growth, progression, and immunosuppression. In this study, we revealed that gold nanoparticles (Au NPs) with a size of 30 nm disrupted NLRP3 inflammasome, but not other inflammasomes, in bone marrow-derived macrophages through abrogating NLRP3-NEK7 interactions mediated by reactive oxygen species (ROS). Density functional theory (DFT) calculations provided insights into the mechanism underlying the exceptional ROS scavenging capabilities of Au NPs. Additionally, when coupled with H6, a small peptide targeting MDSCs, Au NPs demonstrated the capacity to effectively reduce IL-1β levels and diminish the MDSCs population in tumor microenvironment, leading to enhanced T cell activation and increased immunotherapeutic efficacy in mouse tumor models that are sensitive and resistant to PD-1 inhibition. Our findings unraveled a novel approach wherein peptide-modified Au NPs relieved the suppressive impact of the tumor microenvironment by inhibiting MDSCs-mediated IL-1β release, which is the first time reported the employing a nanostrategy at modulating MDSCs to reverse the immunosuppressive microenvironment and may hold promise as a potential therapeutic agent for cancer immunotherapy.

中文翻译：

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靶向 MDSC 的金纳米颗粒通过抑制 NLRP3 炎症小体增强 PD-1 肿瘤免疫治疗

骨髓源性抑制细胞（MDSC）在限制免疫治疗策略功效的免疫逃逸机制中发挥着至关重要的作用。在肿瘤微环境中，NLRP3 炎症小体驱动的白细胞介素 1β (IL-1β) 产生可抑制抗肿瘤免疫反应，促进肿瘤生长、进展和免疫抑制。在这项研究中，我们发现尺寸为 30 nm 的金纳米颗粒 (Au NPs) 通过消除活性氧 (ROS) 介导的 NLRP3-NEK7 相互作用，破坏骨髓源性巨噬细胞中的 NLRP3 炎症小体，但不会破坏其他炎症小体。密度泛函理论 (DFT) 计算提供了对 Au 纳米颗粒卓越的 ROS 清除能力背后机制的见解。此外，当与 H6（一种针对 MDSC 的小肽）结合时，Au NP 能够有效降低 IL-1β 水平并减少肿瘤微环境中的 MDSC 数量，从而增强 T 细胞活化并提高小鼠肿瘤模型中的免疫治疗效果。对 PD-1 抑制敏感且具有抵抗力。我们的研究结果揭示了一种新方法，其中肽修饰的Au NPs通过抑制MDSCs介导的IL-1β释放来减轻肿瘤微环境的抑制影响，这是首次报道采用纳米策略调节MDSCs来逆转免疫抑制微环境，并可能有望成为癌症免疫疗法的潜在治疗剂。