Deng Xi, Liu Tianzhi, Zhu Yutong, Chen Jufeng, Song Ze, Shi Zhangpeng, Chen Hangrong
State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai, 200050, PR China.
Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, 100049, PR China.
Bioact Mater. 2023 Dec 3;33:483-496. doi: 10.1016/j.bioactmat.2023.11.017. eCollection 2024 Mar.
Limited by low tumor immunogenicity and the immunosuppressive tumor microenvironment (TME), triple-negative breast cancer (TNBC) has been poorly responsive to immunotherapy so far. Herein, a Ca & Mn dual-ion hybrid nanostimulator (CMS) is constructed to enhance anti-tumor immunity through ferroptosis inducing and innate immunity awakening, which can serve as a ferroptosis inducer and immunoadjuvant for TNBC concurrently. On one hand, glutathione (GSH) depletion and reactive oxygen species (ROS) generation can be achieved due to the mixed valence state of Mn in CMS. On the other hand, as an exotic Ca supplier, CMS causes mitochondrial Ca overload, which further amplifies the oxidative stress. Significantly, tumor cells undergo ferroptosis because of the inactivation of glutathione peroxidase 4 (GPX4) and accumulation of lipid peroxidation (LPO). More impressively, CMS can act as an immunoadjuvant to awaken innate immunity by alleviating intra-tumor hypoxia and Mn-induced activation of the STING signaling pathway, which promotes polarization of tumor-associated macrophages (TAMs) and activation of dendritic cells (DCs) for antigen presentation and subsequent infiltration of tumor-specific cytotoxic T lymphocytes (CTLs) into tumor tissues. Taken together, this work demonstrates a novel strategy of simultaneously inducing ferroptosis and awakening innate immunity, offering a new perspective for effective tumor immunotherapy of TNBC.
受低肿瘤免疫原性和免疫抑制性肿瘤微环境（TME）的限制，三阴性乳腺癌（TNBC）迄今为止对免疫疗法的反应一直不佳。在此，构建了一种钙锰双离子混合纳米刺激器（CMS），通过诱导铁死亡和唤醒先天免疫来增强抗肿瘤免疫力，其可同时作为TNBC的铁死亡诱导剂和免疫佐剂。一方面，由于CMS中锰的混合价态，可实现谷胱甘肽（GSH）耗竭和活性氧（ROS）生成。另一方面，作为一种外来的钙供应者，CMS会导致线粒体钙超载，这进一步放大了氧化应激。值得注意的是，由于谷胱甘肽过氧化物酶4（GPX4）失活和脂质过氧化（LPO）积累，肿瘤细胞会发生铁死亡。更令人印象深刻的是，CMS可作为一种免疫佐剂，通过减轻肿瘤内缺氧和锰诱导的STING信号通路激活来唤醒先天免疫，这促进肿瘤相关巨噬细胞（TAM）极化和树突状细胞（DC）激活以进行抗原呈递，以及随后肿瘤特异性细胞毒性T淋巴细胞（CTL）浸润到肿瘤组织中。综上所述，这项工作展示了一种同时诱导铁死亡和唤醒先天免疫的新策略，为TNBC的有效肿瘤免疫治疗提供了新的视角。
