Bioactive Vanadium Disulfide Nanostructure with “Dual” Antitumor Effects of Vanadate and Gas for Immune-Checkpoint Blockade-Enhanced Cancer Immunotherapy

Bioactive inorganic nanomaterials and the biological effects of metal ions have attracted extensive attention in tumor therapy in recent years. Vanadium (V), as a typical bioactive metal element, regulates a variety of biological functions. However, its role in antitumor therapy remains to be revealed. Herein, biodegradable vanadium disulfide (VS2) nanosheets (NSs) were prepared as a responsive gas donor and bioactive V source for activating cancer immunotherapy in combination with immune-checkpoint blockade therapy. After PEGylation, VS2-PEG exhibited efficient glutathione (GSH) depletion and GSH-activated hydrogen sulfide (H2S) release. Exogenous H2S caused lysosome escape and reduced adenosine triphosphate (ATP) synthesis in tumor cells by interfering with the mitochondrial membrane potential and inducing acidosis. In addition, VS2-PEG degraded into high-valent vanadate, leading to Na+/K+ ATPase inhibition, potassium efflux, and interleukin (IL)-1β production. Together with further induction of ferroptosis and immunogenic cell death, a strong antitumor immune response was stimulated by reversing the immunosuppressive tumor microenvironment. Moreover, the combined treatment of VS2-PEG and α-PD-1 amplified antitumor therapy, significantly suppressed tumor growth, and further elicited robust immunity to effectively defeat tumors. This work highlights the biological effects of vanadium for application in cancer treatment.