A metabolic intervention strategy for enhanced ferroptosis/cuproptosis activation and boosted anti-tumor immunity

Accumulating evidence suggests that cupreous nanomaterials are capable to trigger the cuproptosis and ferroptosis of malignant cells, providing possibilities for cancer therapy. However, how to realize synchronous cuproptosis and ferroptosis sensitization remains a research gap. Considering the interplays between cuproptotic and ferroptotic pathways, the manipulation of their common regulators provides a feasible approach; based on this, we innovatively propose a metabolic intervention strategy to synchronously reinforce tumor cells’ cuproptosis/ferroptosis susceptibility. STF-31 is utilized to inhibit glycolysis and compensatory nicotinamide adenine dinucleotide (NAD⁺) metabolism, which is encapsulated in the lipid bilayers of a composited copper (Cu)-tannic acid (TA) network/liposome system. The as-prepared nanosystem (SCu/L) significantly decreases intracellular glucose, NAD⁺, reduced nicotinamide adenine dinucleotide phosphate (NADPH) and adenosine triphosphate (ATP) levels and inhibits Cu-ATPase activity, thus inhibiting GSH synthesis and Cu efflux and eventually reinforcing both cuproptosis and ferroptosis. Besides, the glycolysis inhibition effect also helps to remodulate tumor immune microenvironment (TIME), finally boosting anti-tumor immunity together with immunogenic cell death (ICD)-activated T cell immunity. Taken together, this work presents a simple yet effective metabolic intervention strategy for synchronously sensitizing tumor cells to cuproptosis and ferroptosis induced by a cupreous system, providing a feasible pattern for reinforcing the tumoricidal efficiency of cupreous formulations and expanding the prospective applications of ferroptosis/cuproptosis-based therapy.