Liu Li, Fu Shengxiang, Gu Haojie, Li Yangqian, Zhu Guonian, Ai Hua, Li Weimin
Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, P. R. China.
State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Chengdu 610041, P. R. China.
ACS Nano. 2025 Jan 21;19(2):2726-2741. doi: 10.1021/acsnano.4c15115. Epub 2025 Jan 7.
The stimulator of interferon genes (STING) pathway exhibits great potential in remodeling the immunosuppressive tumor microenvironment and initiating antitumor immunity. However, how to effectively activate STING and avoid undesired toxicity after systemic administration remains challenging. Herein, platinum(IV)-backboned polymer prodrug-coated manganese oxide nanoparticles (DHP/MnONP) with pH/redox dual responsive properties are developed to precisely release cisplatin and Mn in the tumor microenvironment and synergistically amplify STING activation. , we demonstrate that DHP/MnONP can effectively induce tumor cell DNA damage and leak into the cytoplasm, cooperating with Mn to promote STING activation and significantly upregulate the expression of proinflammatory cytokines. Additionally, DHP/MnONP can selectively release cisplatin and Mn to mediate tumor killing while reducing toxicity to normal cells. , DHP/MnONP exerted increased therapeutic efficacy by inducing STING activation and initiating robust antitumor immunity. Specifically, DHP/MnONP effectively skewed tumor-associated macrophages toward a proinflammatory phenotype and upregulated the expression of proinflammatory cytokines in tumors by up to 99-fold relative to the control. And the infiltration of CD8 T cells was also significantly increased. When STING signaling was blocked, the antitumor effects and immunostimulatory efficacy of DHP/MnONP were significantly inhibited. Moreover, DHP/MnONP possess the advantage of enhanced tumor homing and retention, resulting in stronger and longer-lasting anticancer effects. Overall, DHP/MnONP provide a potential platform for potentiating cancer chemoimmunotherapy and hold promise for precision treatment.
干扰素基因刺激因子（STING）通路在重塑免疫抑制性肿瘤微环境和启动抗肿瘤免疫方面具有巨大潜力。然而，如何在全身给药后有效激活STING并避免不良毒性仍然具有挑战性。在此，开发了具有pH/氧化还原双响应特性的铂（IV）骨架聚合物前药包被的氧化锰纳米颗粒（DHP/MnONP），以在肿瘤微环境中精确释放顺铂和锰，并协同增强STING激活。我们证明，DHP/MnONP可以有效诱导肿瘤细胞DNA损伤并泄漏到细胞质中，与锰协同促进STING激活，并显著上调促炎细胞因子的表达。此外，DHP/MnONP可以选择性释放顺铂和锰来介导肿瘤杀伤，同时降低对正常细胞的毒性。因此，DHP/MnONP通过诱导STING激活和启动强大的抗肿瘤免疫发挥了增强的治疗效果。具体而言，DHP/MnONP有效地使肿瘤相关巨噬细胞向促炎表型倾斜，并且相对于对照组，肿瘤中促炎细胞因子的表达上调了高达99倍。并且CD8 T细胞的浸润也显著增加。当STING信号被阻断时，DHP/MnONP的抗肿瘤作用和免疫刺激功效被显著抑制。此外，DHP/MnONP具有增强的肿瘤归巢和滞留优势，从而产生更强、更持久的抗癌效果。总体而言，DHP/MnONP为增强癌症化学免疫疗法提供了一个潜在平台，并有望实现精准治疗。
