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

Abstract

AbstractPrevious 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.