Near‐infrared Activatable Copper Nanoplatforms Synergize with the 5‐Azacytidine Prodrug to Potentiate Cuproptosis

Abstract Cuproptosis, a newly discovered cell death modality, is gaining recognition for its crucial role in antitumor therapy. Here, we demonstrated that Ferredoxin 1 (FDX1), a key gene involved in cuproptosis, is negatively correlated with malignancy and T‐cell exhaustion in head and neck squamous cell carcinoma (HNSCC). Based on these findings, we developed near‐infrared (NIR) light‐controlled nanoparticles (NPs), CuD@PM, which can selectively deliver copper to HNSCC cells and induce cuproptosis in the presence of microneedles loaded with triacetylated azacitidine (TAc‐AzaC) and 808 nm laser irradiation. Intravenous administration of these NPs significantly suppressed tumor growth in HNSCC animal models and enhanced the antitumor immune response. The NIR‐controlled activation of cuproptosis offers great potential as a safe, targeted, and image‐guided antitumor therapy for HNSCC.