Department of Radiation Oncology and Molecular Radiation Sciences, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21231, United States.
The Hormel Institute, University of Minnesota, Austin, Minnesota 55912, United States.
ACS Nano. 2024 Apr 16;18(15):10509-10526. doi: 10.1021/acsnano.3c12064. Epub 2024 Apr 2.
Systemic exposure to starch-coated iron oxide nanoparticles (IONPs) can stimulate antitumor T cell responses, even when little IONP is retained within the tumor. Here, we demonstrate in mouse models of metastatic breast cancer that IONPs can alter the host immune landscape, leading to systemic immune-mediated disease suppression. We report that a single intravenous injection of IONPs can inhibit primary tumor growth, suppress metastases, and extend survival. Gene expression analysis revealed the activation of Toll-like receptor (TLR) pathways involving signaling via Toll/Interleukin-1 receptor domain-containing adaptor-inducing IFN-β (TRIF), a TLR pathway adaptor protein. Requisite participation of TRIF in suppressing tumor progression was demonstrated with histopathologic evidence of upregulated IFN-regulatory factor 3 (IRF3), a downstream protein, and confirmed in a TRIF knockout syngeneic mouse model of metastatic breast cancer. Neither starch-coated polystyrene nanoparticles lacking iron, nor iron-containing dextran-coated parenteral iron replacement agent, induced significant antitumor effects, suggesting a dependence on the type of IONP formulation. Analysis of multiple independent clinical databases supports a hypothesis that upregulation of TLR3 and IRF3 correlates with increased overall survival among breast cancer patients. Taken together, these data support a compelling rationale to re-examine IONP formulations as harboring anticancer immune (nano)adjuvant properties to generate a therapeutic benefit without requiring uptake by cancer cells.
系统暴露于淀粉包覆的氧化铁纳米粒子（IONP）可刺激抗肿瘤 T 细胞反应，即使肿瘤内很少保留 IONP。在这里，我们在转移性乳腺癌的小鼠模型中证明，IONP 可以改变宿主免疫景观，导致全身性免疫介导的疾病抑制。我们报告说，单次静脉注射 IONP 可以抑制原发性肿瘤生长、抑制转移并延长存活期。基因表达分析显示，涉及 Toll/白细胞介素-1 受体域包含衔接诱导 IFN-β（TRIF）信号转导的 Toll 样受体（TLR）途径被激活，TRIF 是一种 TLR 途径衔接蛋白。通过上调 IFN 调节因子 3（IRF3）的组织病理学证据证实了 TRIF 在抑制肿瘤进展中的必需参与，IRF3 是下游蛋白，并且在转移性乳腺癌的 TRIF 敲除同基因小鼠模型中得到了证实。既不含铁的淀粉包覆聚苯乙烯纳米粒子，也不含铁的右旋糖酐包覆的肠外铁替代剂，都没有引起明显的抗肿瘤作用，这表明对 IONP 制剂类型有依赖性。对多个独立的临床数据库的分析支持了这样一种假设，即 TLR3 和 IRF3 的上调与乳腺癌患者总体生存率的提高相关。总之，这些数据支持了一个强有力的理论，即重新检查 IONP 制剂作为具有抗癌免疫（纳米）佐剂特性的制剂，在不要求癌细胞摄取的情况下产生治疗益处。
