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

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. Co‐delivery of the NIR‐II photosensitizer H7‐Cu‐BPE and the ROS‐responsive copper ionophore DTC‐BA enables targeted activation of cuproptosis in oral carcinoma. Upon 808 nm irradiation, DTC chelates Cu2+ from H7‐Cu‐BPE to form Cu(DTC)2, which is reduced by endogenous FDX1 to produce Cu+ and promote cuproptosis. The addition of 5‐Azacytidine further replenished cellular FDX1, sustaining cuproptosis and enhancing both tumor suppression and antitumor immunity.