在免疫“冷”肿瘤中诱导炎症反应的治疗策略有可能改善免疫治疗结果。药理学激活 STING 通路可诱导先天免疫，从而增强肿瘤免疫原性。在这里，我们开发了一种具有肿瘤限制药理学的纳米佐剂，可以快速激活 STING 并重塑肿瘤微环境 (TME)。非核苷酸 STING 激动剂 MSA-2 经过化学工程改造，具有由不同长度的饱和烃链连接的哌嗪基序，以产生可电离的前药，并进一步开发为纳米佐剂。与最先进的脂质体相比，纳米佐剂在循环中的滞留时间延长，并改善了肿瘤内的递送。在酸性 TME 中，纳米佐剂经过聚乙二醇去屏蔽，能够有效外渗并渗透到肿瘤中。与此同时，STING 前药从内切/溶酶体区室中逸出，分配到胞质溶胶中，用于自发酯酶催化的药物激活。在同基因和化学诱导结直肠癌的小鼠模型中，纳米颗粒治疗激发了强大的 STING 介导的抗肿瘤免疫，将肿瘤免疫景观从免疫抑制转变为杀肿瘤。此外，纳米佐剂在三阴性乳腺癌中表现出抗肿瘤功效，通过添加免疫检查点抑制剂进一步增强了这种功效。总的来说，这项研究证明了 STING 激活纳米佐剂的安全性和免疫刺激作用，支持对这种 STING 免疫疗法单独以及与其他免疫疗法联合进行的临床评估。

Therapeutic strategies that induce inflammatory responses in immunologically "cold" tumors have the potential to improve immunotherapeutic outcomes. Pharmacologically activating the STING pathway induces innate immunity, subsequently enhancing tumor immunogenicity. Here, we developed a nanoadjuvant with tumor-restricted pharmacology that rapidly activated STING and reshaped the tumor microenvironment (TME). The non-nucleotide STING agonist MSA-2 was chemically engineered with a piperazine motif linked by a saturated hydrocarbon chain of varying lengths to produce ionizable prodrugs that were further developed into nanoadjuvants. Compared with state-of-the-art liposomes, the nanoadjuvant displayed prolonged retention in the circulation and improved intratumoral delivery. In the acidic TME, the nanoadjuvant underwent polyethylene glycol deshielding, enabling efficient extravasation and penetration into tumors. Concomitantly, the STING prodrug escaped from the endo/lysosome compartment to partition into the cytosol for spontaneous esterase-catalyzed drug activation. In mouse models of syngeneic and chemically induced colorectal cancers, nanoparticle treatment provoked robust STING-mediated antitumor immunity, shifting the tumor immune landscape from immunosuppressed to tumoricidal. Additionally, the nanoadjuvant demonstrated antitumor efficacy in triple-negative breast cancer, which was further enhanced by the addition of immune checkpoint inhibitors. Collectively, this study demonstrates the safety and immune stimulating effects of a STING-activating nanoadjuvant, supporting the clinical evaluation of this STING immunotherapeutic alone and in combination with other immunotherapies.