The efficacy of STING (stimulator of interferon genes) agonists is due to various factors, primarily inefficient intracellular delivery, low/lack of endogenous STING expression in many tumours, and a complex balance between tumour control and progression. Here we report a universal STING mimic (uniSTING) based on a polymeric architecture. UniSTING activates STING signalling in a range of mouse and human cell types, independent of endogenous STING expression, and selectively stimulates tumour control IRF3/IFN-I pathways, but not tumour progression NF-κB pathways. Intratumoural or systemic injection of uniSTING-mRNA via lipid nanoparticles (LNPs) results in potent antitumour efficacy across established and advanced metastatic tumour models, including triple-negative breast cancer, lung cancer, melanoma and orthotopic/metastatic liver malignancies. Furthermore, uniSTING displays an effective antitumour response superior to 2′3′-cGAMP and ADU-S100. By favouring IRF3/IFN-I activity over the proinflammatory NF-κB signalling pathway, uniSTING promotes dendritic cell maturation and antigen-specific CD8⁺ T-cell responses. Extracellular vesicles released from uniSTING-treated tumour cells further sensitize dendritic cells via exosome-containing miRNAs that reduced the immunosuppressive Wnt2b, and a combination of LNP-uniSTING-mRNA with α-Wnt2b antibodies synergistically inhibits tumour growth and prolongs animal survival. Collectively, these results demonstrate the LNP-mediated delivery of uniSTING-mRNA as a strategy to overcome the current STING therapeutic barriers, particularly for the treatment of multiple cancer types in which STING is downregulated or absent.

STING（干扰素基因刺激剂）激动剂的功效取决于多种因素，主要是细胞内递送效率低下、许多肿瘤中内源性 STING 表达低/缺乏，以及肿瘤控制和进展之间的复杂平衡。在这里，我们报告了一种基于聚合物结构的通用 STING 模拟物 (uniSTING)。UniSTING 可激活一系列小鼠和人类细胞类型中的 STING 信号传导，不依赖于内源性 STING 表达，并选择性刺激肿瘤控制 IRF3/IFN-I 通路，但不刺激肿瘤进展 NF-κB 通路。通过脂质纳米颗粒 (LNP) 进行肿瘤内或全身注射 uniSTING-mRNA，可在已建立的和晚期转移性肿瘤模型中产生有效的抗肿瘤功效，包括三阴性乳腺癌、肺癌、黑色素瘤和原位/转移性肝脏恶性肿瘤。此外，uniSTING 显示出优于 2'3'-cGAMP 和 ADU-S100 的有效抗肿瘤反应。通过促进 IRF3/IFN-I 活性而非促炎 NF-κB 信号通路，uniSTING 可促进树突状细胞成熟和抗原特异性 CD8 ⁺ T 细胞反应。经过 uniSTING 处理的肿瘤细胞释放的细胞外囊泡通过含有外泌体的 miRNA 进一步使树突状细胞敏感，从而减少免疫抑制性 Wnt2b，LNP-uniSTING-mRNA 与 α-Wnt2b 抗体的组合可协同抑制肿瘤生长并延长动物存活时间。总的来说，这些结果证明 LNP 介导的 uniSTING-mRNA 递送是克服当前 STING 治疗障碍的策略，特别是对于治疗 STING 下调或缺失的多种癌症类型。