A Vanadium-Based Nanoplatform Synergizing Ferroptotic-like Therapy with Glucose Metabolism Intervention for Enhanced Cancer Cell Death and Antitumor Immunity

Ferroptosis activation has been considered a mighty weapon for cancer treatment, and growing attention is being paid to reinforcing tumor cells' sensitivity to ferroptosis. However, the existence of certain ferroptosis resistance mechanisms, especially the abnormal metabolism of tumor cells, has long been underestimated. We propose an enhanced ferroptosis-activating pattern via regulating tumor cells' glycometabolism and construct a nanoplatform named PMVL, which is composed of lonidamine (LND)-loaded tannic acid coordinated vanadium oxides with the camouflage of PD-L1 inhibiting peptide-modified tumor cell membrane. This work reveals that the mixed valence of vanadium (V^IV and V^V) in PMVL triggers ferroptosis due to the self-cyclic valence alteration of V, the process of which generates ^•OH for lipid peroxide accumulation (V^IV → V^V) and depletes glutathione (GSH) for glutathione peroxidase (GPX4) deactivation (V^V → V^IV). Notably, LND strengthens ferroptosis by dual suppression of glycolysis (decreasing ATP supply) and the pentose phosphate pathway (decreasing NADPH production), causing anabatic GSH consumption. Besides, the inhibited glycolysis generates less intracellular lactic acid and alleviates the acidity of tumor microenvironment, preventing immunosuppressive M2 macrophage polarization. In vitro and in vivo data demonstrate the glycometabolism-intervention-enhanced ferroptosis and boosted immunity activation, potentially providing opportunities and possibilities for synergetic cancer therapy.