肿瘤微环境
癌症研究
合成致死
PARP抑制剂
卵巢癌
免疫疗法
免疫系统
体内
DNA损伤
免疫检查点
DNA修复
奥拉帕尼
细胞周期检查点
同源重组
癌细胞
聚ADP核糖聚合酶
材料科学
封锁
刺
细胞毒性
干扰素
癌症免疫疗法
免疫原性细胞死亡
细胞凋亡
医学
癌症
细胞培养
程序性细胞死亡
生物
细胞
信号转导
抗药性
细胞生长
药理学
作者
He Zhang,Yi Sun,Lingpu Zhang,Meifang Shen,Xiaowei Tong,Dan Zhao,Haihua Xiao,Bin Li
标识
DOI:10.1002/adma.202512962
摘要
Overcoming the immunosuppressive tumor microenvironment and therapeutic resistance remains a significant challenge in ovarian cancer treatment. In this study, a glutathione-responsive polymeric nanoparticle platform for the co-delivery of the USP1 inhibitor SJB3-019A and the PARP inhibitor Niraparib is developed. This system synergistically enhances DNA damage accumulation, suppresses homologous recombination repair, and robustly activate the STING signaling pathway, leading to enhanced type I interferon responses and mitigation of immune evasion. Mechanistically, USP1 inhibition significantly impairs DNA repair, amplifying the synthetic lethality of PARP inhibition and promoting immunogenic cell death. In vivo studies demonstrated precise, glutathione-responsive drug release and substantial tumor accumulation of the nanoparticles, resulting in remarkable antitumor efficacy in murine ovarian cancer models. Importantly, this combinational approach effectively remodels the tumor microenvironment by increasing CD8⁺ T cell infiltration and enhancing tumor sensitivity to immune checkpoint blockade therapies. This innovative strategy targeting DNA damage responses presents a promising platform for precise and effective ovarian cancer immunotherapy.
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