Ca & Mn dual-ion hybrid nanostimulator boosting anti-tumor immunity via ferroptosis and innate immunity awakening

Xi Deng; Tianzhi Liu; Yutong Zhu; Jufeng Chen; Ze Song; Zhangpeng Shi; Hangrong Chen

doi:10.1016/j.bioactmat.2023.11.017

Ca & Mn dual-ion hybrid nanostimulator boosting anti-tumor immunity via ferroptosis and innate immunity awakening

Bioact Mater. 2023 Dec 3:33:483-496. doi: 10.1016/j.bioactmat.2023.11.017. eCollection 2024 Mar.

Authors

Xi Deng^{1

2}, Tianzhi Liu¹, Yutong Zhu^{1

2}, Jufeng Chen^{1

2}, Ze Song^{1

2}, Zhangpeng Shi^{1

3}, Hangrong Chen^{1

2

4

3}

Affiliations

¹ State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai, 200050, PR China.
² Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, 100049, PR China.
³ Nanotechnology and Intestinal Microecology Research Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, PR China.
⁴ School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, PR China.

Abstract

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 Ca²⁺ supplier, CMS causes mitochondrial Ca²⁺ 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 Mn²⁺-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.

Keywords: Calcium carbonate nanoparticles; Ferroptosis; Immunotherapy; Innate immunity; Manganese; STING signaling pathway.