Glycolysis inhibition-based breakdown of ferroptosis defenses to achieve ferroptosis and immune cascades for antitumor therapy.

Abstract

As a newly identified type of regulated cell death, ferroptosis has attracted considerable attention within cancer treatment research. Nevertheless, tumor cells often evade ferroptosis through defensive mechanisms such as aberrant energy metabolism and elevated glutathione (GSH) levels, which help maintain intracellular redox homeostasis. The potential of targeting energy metabolism to disrupt ferroptosis resistance in cancer treatment has been largely overlooked. In this study, we constructed a purposefully engineered nanoplatform utilizing a hollow metal-organic framework as its foundation (ZIF-90), denoted as ZIF-90-ruthenium (Ru)-Apigenin@Tetradecanol-PEG (ZRATP), to disrupt redox balance and establish a tumor microenvironment (TME) conducive to ferroptosis via glycolysis inhibition. Under simultaneous microwave irradiation and acidic TME conditions, ZRATP gradually releases apigenin and Ru. Apigenin acts as a glycolysis inhibitor by targeting pyruvate kinase M2, thereby reprogramming tumor metabolism to favor ferroptosis. Concurrently, Ru depletes GSH and generates reactive oxygen species, directly disturbing redox homeostasis and initiating ferroptosis. This ferroptotic process not only induces immunogenic cell death but also recruits damage-associated molecular patterns. Glycolysis inhibition further alleviates the immunosuppressive TME and enhances immune cell infiltration. These activated immune cells secrete interferon-γ, which downregulates the cystine/glutamate antiporter (system Xc-), thereby further promoting ferroptosis. Together, these effects establish a self-amplifying cycle where metabolic intervention and immune activation synergistically enhance ferroptosis in tumor cells. ZRATP represents a novel strategic platform for the treatment of malignant tumors.