Dual Metal Nanoflower Oxygen Pump Microneedles Based on Cuproptosis and STING Pathway Activation for Cancer Immunotherapy

Abstract

Immunotherapy is a promising new approach for tumor treatment. However, its clinical application is hindered by insufficient immunogenicity, hypoxia, and immunosuppressive tumor microenvironment (TME). Here, oxygen pump microneedles (OPMNs) loaded with zinc-doped copper sulfide nanoflowers (ZCS NFs) and PD-L1 small interfering RNA (siPD-L1) (OPMNs-ZCS@siPD-L1) are developed for boosting tumor immunotherapy. OPMN-ZCS@siPD-L1 enhances tumor immunogenicity through ZCS NFs by inducing cuproptosis, reverses TME through siPD-L1, and promotes drug penetration, and ameliorates hypoxia through oxygen bubbles. More importantly, cuproptosis-induced mitochondrial DNA (mtDNA) together with Zn²⁺ co-activate the STING pathway, triggering a robust immune response. OPMN-ZCS@siPD-L1 increases the sensitivity to cuproptosis and induces immunogenic cell death (ICD) in vivo and in vitro, which significantly inhibits tumor progression and metastasis. The novel strategy of “increasing the throttle” (cuproptopsis-mediated STING activation & ICD effect) combined with “releasing the brake” (PD-L1 inhibition & hypoxia improvement) provides a new approach for enhancing percutaneous tumor immunotherapy.