Zhong Nan, Zu Ziyue, Lu Yishi, Sha Xuan, Li Yang, Liu Yang, Lu Shangyu, Luo Xi, Zhou Yan, Tao Jun, Wu Feiyun, Teng Zhaogang, Tang Yuxia, Wang Shouju
Laboratory of Molecular Imaging, Department of Radiology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China.
Department of Interventional Radiology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China.
Acta Biomater. 2025 Apr 26. doi: 10.1016/j.actbio.2025.04.040.
Activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway could effectively initiate antitumor immunity in triple-negative breast cancer. However, current nuclear DNA-mediated activation of STING pathway remains constrained by the tight protection of nuclear membrane and histones, highlighting the need for new strategies to enhance its efficacy. Mitochondrial DNA (mtDNA), in contrast, is more vulnerable to damage. Herein, our nanoplatforms exploited the high glutathione (GSH) environment characteristic of tumors to release abundant Mn, which induced mitochondrial dysfunction and the release of endogenous mtDNA. The released mtDNA, in conjunction with Mn itself functioning as a strong cGAS agonist, effectively activated cGAS-STING pathway. Consequently, the cGAS-STING-dependent secretion of type I interferon successively enhanced the maturation of dendritic cells and cross-priming of CD8 T cells. In a poorly immunogenic 4T1 tumor model, TPP-MMONs efficiently primed systemic antitumor immunity and significantly enhanced the therapeutic efficacy of αPD-L1 therapy, suppressing tumor growth in both localized and metastatic tumor models. These findings provided an innovative and straightforward strategy to enhance TNBC immunogenicity by targeting mitochondrial damage to induce mtDNA-mediated cGAS-STING activation, thereby sensitizing tumors to immune checkpoint inhibitor therapy. STATEMENT OF SIGNIFICANCE: The cGAS-STING pathway is a promising target for overcoming immunoresistance in TNBC. However, current nuclear DNA-based activation strategies are limited by the tight protection of nuclear membrane and histones. Herein, we reported novel manganese-rich, mitochondria-targeting nanoplatforms (TPP-MMONs), which can release abundant Mn²⁺ and significantly induce mitochondrial dysfunction, leading to the release of mtDNA. As a result, the nanoplatforms can effectively stimulate the cGAS-STING pathway, thereby enhancing immune responses and improving the therapeutic efficacy of αPD-L1 therapy, offering new insights into TNBC treatments.
环磷酸鸟苷-腺苷酸合成酶-干扰素基因刺激物（cGAS-STING）通路的激活可有效启动三阴性乳腺癌的抗肿瘤免疫。然而，目前通过核DNA介导的STING通路激活仍受限于核膜和组蛋白的严密保护，这凸显了需要新策略来提高其疗效。相比之下，线粒体DNA（mtDNA）更容易受到损伤。在此，我们的纳米平台利用肿瘤高谷胱甘肽（GSH）环境的特点释放大量锰，锰诱导线粒体功能障碍并释放内源性mtDNA。释放的mtDNA，连同本身作为强效cGAS激动剂的锰，有效激活cGAS-STING通路。因此，cGAS-STING依赖的I型干扰素分泌相继增强了树突状细胞的成熟和CD8 T细胞的交叉启动。在免疫原性较差的4T1肿瘤模型中，TPP-MMONs有效启动全身抗肿瘤免疫，并显著增强αPD-L1疗法的治疗效果，在局部和转移性肿瘤模型中均抑制肿瘤生长。这些发现提供了一种创新且直接的策略，即通过靶向线粒体损伤诱导mtDNA介导的cGAS-STING激活来增强三阴性乳腺癌的免疫原性，从而使肿瘤对免疫检查点抑制剂疗法敏感。重要性声明：cGAS-STING通路是克服三阴性乳腺癌免疫抗性的一个有前景的靶点。然而，目前基于核DNA的激活策略受到核膜和组蛋白严密保护的限制。在此，我们报道了新型的富含锰的线粒体靶向纳米平台（TPP-MMONs），其可释放大量Mn²⁺并显著诱导线粒体功能障碍，导致mtDNA释放。结果，该纳米平台可有效刺激cGAS-STING通路，从而增强免疫反应并提高αPD-L1疗法的治疗效果，为三阴性乳腺癌治疗提供了新见解。
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