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  2. Augmenting Antitumor Immune Effects through the Coactivation of cGAS-STING and NF-κB Crosstalk in Dendritic Cells and Macrophages by Engineered Manganese Ferrite Nanohybrids

Augmenting Antitumor Immune Effects through the Coactivation of cGAS-STING and NF-κB Crosstalk in Dendritic Cells and Macrophages by Engineered Manganese Ferrite Nanohybrids

  • ACS Appl Mater Interfaces. 2025 Mar 5;17(9):13375-13390. doi: 10.1021/acsami.4c18570.
Heying Chen 1 2 Dongqing Wang 3 4 Jiahe Liu 1 Jun Chen 5 Yi Hu 6 Yilu Ni 1
Affiliations

Affiliations

  • 1 The Key Laboratory of Chinese Ministry of Education in Laboratory Medical Diagnostics, College of Laboratory Medicine, Chongqing Medical University, #1 Yixueyuan Road, Yuzhong District, Chongqing 400016, China.
  • 2 Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, West China Second University Hospital, Sichuan University, Chengdu 610041, China.
  • 3 Sichuan Provincial Key Laboratory for Human Disease Gene Study and the Center for Medical Genetics, Department of Laboratory Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China.
  • 4 Department of Chemistry, City University of Hong Kong, 83 Tat Chee Avenue, Kowloon, Hong Kong 999077, China.
  • 5 Chinese Academy of Sciences Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics and University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100049, China.
  • 6 State Key Laboratory of Complex Severe and Rare Diseases, Biomedical Engineering Facility of National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
Abstract

The specific activation of dendritic cells (DCs) and tumor-associated macrophages (TAMs) can activate innate and adaptive immune responses to reverse the tumor immunosuppressive microenvironment. In this study, manganese ferrite nanohybrid MnFe5O8@(M1M-DOX) is synthesized to activate cGAS-STING and NF-κB crosstalk in DCs and TAMs. MnFe5O8, as the source of Fe2+/Fe3+ and Mn2+, is encapsulated with a microdose of doxorubicin (DOX) using an M1 macrophage cytomembrane. Fe2+/Fe3+ and DOX can cooperatively induce tumorous Ferroptosis, triggering immunogenic cell death (ICD) that exposes tumor antigens. The release of Fe2+/Fe3+ and Mn2+ has intrinsic dual-immunomodulatory effects on the activation of DCs and the reprogramming of TAMs from the M2 to M1 phenotype. Briefly, Fe2+/Fe3+ activates the NF-κB signaling pathway to trigger the activation of STING signaling. Meanwhile, Mn2+ further enhances the activation of STING and stimulates NF-κB in a cascade-activating manner. Thus, the mutually reinforcing dual activation of cGAS-STING and NF-κB crosstalk prompts the strong maturation of DCs and TAMs, synergistically promoting the infiltration of T cells to inhibit primary tumor growth and localized recurrence. This work proposes a strategy for delivering immunomodulatory metal ions in nanoalloy and harnessing the activation of multisignaling pathways in antigen-presenting cells (APCs) to provide perspectives for tumor immunotherapy.

Keywords

NF-κB; cGAS-STING; dendritic cell; macrophage; manganese ferrite nanoalloy; tumor immunotherapy.

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