Abstract

The role of amino acid metabolism in tumor metastasis remains poorly understood, particularly in bone metastasis. Here, we demonstrate that tumor cell-derived γ-aminobutyric acid (GABA) plays a central role in promoting spinal metastasis (SM) of lung cancer. GABA indirectly promotes tumor cell migration and invasion through immune cells, suggesting that GABA inhibition may represent a promising therapeutic strategy for modulating tumor-immune crosstalk. Therefore, an ionic suppression strategy has been proposed, involving the synthesis of a class of metal-organic framework nanoparticles (ZIF-8@18-C-6) to inhibit the function of GABA. Our results demonstrate that ZIF-8@18-C-6 hydrolyze in an acidic environment to produce 18-C-6 and zinc ions. 18-C-6 significantly reduces extracellular potassium ion (K + ) levels, consequently decreasing GABA concentration. Simultaneously, zinc ions inhibit the γ subunit of GABA A receptors, resulting in dual suppression of GABA signaling. Both effects synergistically enhance antitumor immunity in vitro and in vivo, thereby suppressing metastasis. In summary, this approach represents a novel strategy for treating SM of lung cancer through ion-mediated GABA inhibition.