Triple Tumor Microenvironment-Responsive Ferroptosis Pathways Induced by Manganese-Based Imageable Nanoenzymes for Enhanced Breast Cancer Theranostics.

Previous studies have found that activated CD8+ T cells secrete elevated levels of interferon-gamma (IFN-γ) to trigger ferroptosis in tumor cells. However, IFN-γ-mediated ferroptosis is induced at low levels in tumor cells because of the limited IFN-γ secreted by CD8+ T cells in the immunosuppressive tumor microenvironment. Recent studies have shown that manganese ion can activate the cyclic guanosine monophosphate-adenosine monophosphate (GMP-AMP) synthase/stimulator of interferon genes (cGAS-STING) pathway and support adaptive immune responses against tumors, which enhances the level of tumor-infiltrating CD8+ T cells. Therefore, tumor microenvironment-responsive Mn-based nanoenzymes (Mn-based NEs) that activated the cGAS-STING pathway are designed to amplify immune-driven ferroptosis. The multifunctional all-in-one nanoplatform is simply and mildly synthesized by the coordination between Mn3+ ions and 3,3'-dithiodipropionic acid. After intracellular delivery, each component of Mn-based NEs exerts its function. That is, glutathione is depleted through disulfide-thiol exchange and redox pair of Mn3+ /Mn2+ , a hydroxyl radical (·OH) is generated via the Fenton-like reaction to cause ferroptosis, and Mn2+ augments cGAS-STING activity to boost immune-driven ferroptosis. In addition, ferroptosis amplifies Mn2+ -induced immunogenic cell death and initiates the antitumor immune "closed loop" along with immune-driven ferroptosis. Notably, this multifunctional nanoplatform is effective in killing both primary and distant tumors.