Augmenting Antitumor Immune Effects through the Coactivation of cGAS-STING and NF-κB Crosstalk in Dendritic Cells and Macrophages by Engineered Manganese Ferrite Nanohybrids
Heying Chen, Dongqing Wang, Jiahe Liu, Jun Chen, Yi Hu, Yilu Ni
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 MnFe 5 O 8 @(M1M-DOX) is synthesized to activate cGAS-STING and NF-κB crosstalk in DCs and TAMs. MnFe 5 O 8, as the source of Fe 2+ /Fe 3+ and Mn 2+, is encapsulated with a microdose of doxorubicin (DOX) using an M1 macrophage cytomembrane. Fe 2+ /Fe 3+ and DOX can cooperatively induce tumorous ferroptosis, triggering immunogenic cell death (ICD) that exposes tumor antigens. The release of Fe 2+ /Fe 3+ and Mn 2+ has intrinsic dual-immunomodulatory effects on the activation of DCs and the reprogramming of TAMs from the M2 to M1 phenotype. Briefly, Fe 2+ /Fe 3+ activates the NF-κB signaling pathway to trigger the activation of STING signaling. Meanwhile, Mn 2+ 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.