Tao Jiaojiao, Dong Yu, Wang Bingjie, Wang Teng, Zhang Aijia, Li Shuang, Chen Rui, Su Yanguo, Jiang Tianze, Zhao Xia
Key Laboratory of Marine Drugs, Ministry of Education, Shandong Key Laboratory Glycoscience and Glycotherapeutics, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China.
Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center, Qingdao, 266237, China.
Small. 2025 Mar;21(11):e2409187. doi: 10.1002/smll.202409187. Epub 2025 Feb 14.
Immunotherapy is a promising new approach for tumor treatment. However, its clinical application is hindered by insufficient immunogenicity, hypoxia, and immunosuppressive tumor microenvironment (TME). Here, oxygen pump microneedles (OPMNs) loaded with zinc-doped copper sulfide nanoflowers (ZCS NFs) and PD-L1 small interfering RNA (siPD-L1) (OPMNs-ZCS@siPD-L1) are developed for boosting tumor immunotherapy. OPMN-ZCS@siPD-L1 enhances tumor immunogenicity through ZCS NFs by inducing cuproptosis, reverses TME through siPD-L1, and promotes drug penetration, and ameliorates hypoxia through oxygen bubbles. More importantly, cuproptosis-induced mitochondrial DNA (mtDNA) together with Zn co-activate the STING pathway, triggering a robust immune response. OPMN-ZCS@siPD-L1 increases the sensitivity to cuproptosis and induces immunogenic cell death (ICD) in vivo and in vitro, which significantly inhibits tumor progression and metastasis. The novel strategy of "increasing the throttle" (cuproptopsis-mediated STING activation & ICD effect) combined with "releasing the brake" (PD-L1 inhibition & hypoxia improvement) provides a new approach for enhancing percutaneous tumor immunotherapy.
免疫疗法是一种很有前景的肿瘤治疗新方法。然而，其临床应用受到免疫原性不足、缺氧和免疫抑制性肿瘤微环境（TME）的阻碍。在此，开发了负载锌掺杂硫化铜纳米花（ZCS NFs）和程序性死亡受体配体1小干扰RNA（siPD-L1）的氧泵微针（OPMNs）（OPMNs-ZCS@siPD-L1），以增强肿瘤免疫治疗效果。OPMN-ZCS@siPD-L1通过ZCS NFs诱导铜死亡增强肿瘤免疫原性，通过siPD-L1逆转TME，促进药物渗透，并通过氧气泡改善缺氧。更重要的是，铜死亡诱导的线粒体DNA（mtDNA）与锌共同激活干扰素基因刺激蛋白（STING）通路，引发强烈的免疫反应。OPMN-ZCS@siPD-L1在体内和体外均增加了对铜死亡的敏感性并诱导免疫原性细胞死亡（ICD），显著抑制肿瘤进展和转移。“加大油门”（铜死亡介导的STING激活和ICD效应）与“松开刹车”（PD-L1抑制和缺氧改善）相结合的新策略为增强经皮肿瘤免疫治疗提供了一种新方法。
