Key points are not available for this paper at this time.
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. • ZIF-90-Ru-Apigenin@Tetradecanol-PEG (ZRATP) nanoparticles were engineered to enhance the disruption of tumor cell redox homeostasis to promote ferroptosis onset via the Fenton reaction of ruthenium. • Inhibition of glycolysis reverses the glucose metabolic process in tumor cells to create a suitable microenvironment for ferroptosis to occur and at the same time relieve the immunosuppressive microenvironment. • ZRATP nanoparticles achieve self-amplification of ferroptosis and cascading immune-enhancing effects via the DAMPs-IFN-γ-SLC7A11 pathway.
Liu et al. (Mon,) studied this question.