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

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.