Co-delivery of copper chelators and glycolytic inhibitors to disrupt glucose metabolism and inhibit tumor metastasis

The notably heightened copper levels found in cancer underscore the critical involvement of copper ions in tumor progression and metastasis. Consequently, disrupting tumor copper homeostasis is emerging as a novel strategy for cancer treatment. Here, LTMP was constructed using PEG-modified mesoporous polydopamine (MP) loaded with lonidamine (LND, a glycolysis inhibitor) and tetrathiomolybdate (TM, a copper chelator). The utilization of TM as a copper chelator led to a substantial reduction in copper content and inhibited the activity of copper-dependent enzymes, thereby suppressing the oxidative phosphorylation (OXPHOS) process in tumor cells. However, the inhibition of OXPHOS lead to compensatory upregulation of glycolysis, enhancing cellular drug resistance. Therefore, the combination of LND and TM could effectively achieve dual inhibition of glycolysis and OXPHOS, resulting in a substantial enhancement of tumor cell apoptosis. Furthermore, LTMP was found to inhibit the activities of matrix metalloproteinases and lysyl oxidase, thereby impeding the epithelial-mesenchymal transition process and significantly reducing lung tumor metastasis. Additionally, LTMP-based photothermal therapy combined with chemotherapy effectively regulated the tumor microenvironment by reducing immunosuppressive cells and enhancing T lymphocyte infiltration. This work provided new insights for the design of intricate anti-tumor strategies.