Oxygen pump microneedles coupling cuproptosis and disulfidptosis to enhance melanoma immunotherapy.

Cuproptosis and disulfidptosis are new types of programmed cell death with great potential for tumor immunotherapy, but their efficacy is severely restricted by the hypoxic microenvironment and metabolic reprogramming of tumors. Herein, we develop an oxygen-pump microneedle system (CPGH@OMN) co-loading glucose oxidase (GOx) and copper-polyphenol nanoparticles (CP), using sodium percarbonate (SPC) as an in situ oxygen generator and hyaluronic acid (HA) as a tumor-targeting carrier. SPC-mediated oxygen generation acts as a booster to promote deep drug penetration, and downregulates hypoxia-inducible factor-1α (HIF-1α) to alleviate tumor hypoxia. GOx depletes glucose and nicotinamide adenine dinucleotide phosphate (NADPH) to trigger disulfidptosis, which consumes glutathione (GSH) to sensitize cuproptosis. Copper ions from CPGH (CP-GOx-HA) induce robust cuproptosis under the favorable conditions of downregulated HIF-1α and GSH. The suppression of metabolic reprogramming in tumor cells by alleviating hypoxia and depleting NADPH and GSH significantly enhances anti-tumor immune responses. Animal experiment results demonstrate that CPGH@OMN significantly inhibits orthotopic tumor growth and lung metastasis. This oxygen-pump microneedle strategy integrating physical penetration enhancement and metabolic reprogramming provides a novel approach for melanoma immunotherapy.