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Ionizable STING-Activating Nanoadjuvants Enhance Tumor Immunogenicity and Potentiate Immunotherapy Efficacy in Solid Tumors

实体瘤 免疫疗法 癌症研究 癌症免疫疗法 免疫原性 医学 免疫学 癌症 内科学 抗原 工程类 航空航天工程
作者
Shiyun Xian,Xiaona Chen,Sihang Ren,X.M. Chen,Hangxiang Wang
出处
期刊:Cancer Research [American Association for Cancer Research]
卷期号:84 (18): 3044-3057 被引量:4
标识
DOI:10.1158/0008-5472.can-23-3511
摘要

Therapeutic strategies that induce inflammatory responses in immunologically "cold" tumors have the potential to improve immunotherapeutic outcomes. Pharmacologically activating the stimulator of interferon gene (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. 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 tumor microenvironment, 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. Significance: STING-activating nanoadjuvants rationally engineered using an ionizable prodrug approach for systemic administration are well-tolerated and yield durable antitumor immune responses, providing a potential immunotherapeutic strategy to improve cancer treatment.
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