A Dual-Enzyme Delivery System Targeting Lactate Depletion to Induce Disulfidptosis and Activate STING Pathway for Inhibiting Breast Cancer Metastasis.

Lactate, as a key metabolite in the tumor microenvironment (TME), has been reported to inhibit the stimulator of interferon genes (STING) pathway and contribute to immunosuppression and tumor progression. Here, we develop a dual-enzyme delivery system (Fuc@ZIF-GOx-LOx, FZGL) that is coated with fucoidan (Fuc) and loaded with glucose oxidase (GOx) and lactate oxidase (LOx) based on zinc imidazolate framework-90 (ZIF-90), to inhibit breast cancer metastasis by "source interception and downstream blockade" of lactate. FZGL targets tumor cells via Fuc and releases GOx and LOx by the ATP-responsive degradation of ZIF-90. GOx rapidly consumes glucose to block lactate generation from the source ("source interception") and induces disulfidptosis in tumor cells. LOx degrades accumulated lactate ("downstream blockade") to alleviate immunosuppression. FZGL activates the cGAS-STING pathway by damaging mitochondria and inducing mitochondrial DNA (mtDNA) release. Furthermore, lactate depletion can relieve lactate-mediated inhibition of STING signaling, thereby enhancing the anti-tumor immune response. In vivo experiments demonstrate that FZGL significantly promotes T cell infiltration and M1 macrophage polarization, and effectively inhibits the growth and lung metastasis of breast cancer. Our study provides a new approach for metastatic breast cancer treatment through lactate metabolism intervention.