Multifunctional nanocomposites induce mitochondrial dysfunction and glucose deprivation to boost immunogenic ferroptosis for cancer therapy

Ferroptosis is a type of regulated cell death that has attracted much attention owing to its ability to trigger immunogenic cell death (ICD) and enhance immunotherapy. However, ferroptosis can be greatly limited by glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1) antioxidant mechanisms. Herein, to inhibit these antioxidant effects, therapeutic nanocomposites (Cu2_XS-GOx@CaCO3) were developed by attaching glucose oxidase (GOx) and mineralized calcium carbonate to the surface of hollow mesoporous copper sulfide (Cu2_XS, 0 < x < 1). Via GOx-mediated catalysis, intracellular glucose is oxidized to gluconic acid (GA) and hydrogen peroxide (H2O2). Notably, the generated GA stimulates the release of Ca2+ to damage mitochondrial function, while the produced H2O2 enhances the Fenton-like reaction triggered by Cu2_XS, and finally results in the accumulation of reactive oxygen species. Further, the depletion of glucose could damage the pentose phosphate pathway and hinder the synthesis of reduced glutathione (GSH) and the recycling of coenzyme Q10 (CoQ10) into reduced coenzyme Q10 (CoQ10H2), suggesting simultaneous inhibition of the GPX4/ GSH and FSP1/CoQ10H2 pathways. Moreover, the accumulation of reactive oxygen species and the inhibition of antioxidant mechanisms could induce ferroptosis and ICD, followed by the recruitment of cytotoxic T lymphocytes, which synergistically provide an excellent anti-tumour effect. These findings provide a strong rationale for the application of ferroptosis-mediated immunotherapy.