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.