pH‐Responsive Nanoplatform‐Mediated Lipid Hijacking and Metabolic Collapse for Synergistic Starvation‐Immunotherapy

ABSTRACT

Tumor starvation therapy is a promising metabolism‐targeting intervention, yet its efficacy is largely counteracted by lipid droplet (LD)‐driven compensatory metabolism in malignant cells. Existing LDs‐targeted approaches are further hampered by off‐target systemic metabolic disturbances and inherent immunosuppressive adverse effects. Here, we construct a zeolitic imidazolate framework‐8 (ZIF‐8)‐based nanomedicine loaded with 2‐deoxy‐D‐glucose (2‐DG) and surface‐decorated with copper‐tannic acid (Cu‐TA, ZIF‐8/2‐DG@Cu‐TA). This nanosystem reroutes intracellular LDs from tumor cells to adjacent cancer‐associated fibroblasts (CAFs) to realize synergistic tumor starvation and immunotherapy. In the acidic tumor microenvironment, the degradable Cu‐TA coating activates connexin 43 (Cx43) hemichannels on CAFs. After internalization by tumor cells, ZIF‐8/2‐DG releases 2‐DG to suppress glycolysis, while dissociated zinc ions disrupt mitochondrial bioenergetics and further trigger Cx43 hemichannels activation on tumor cells. Fully assembled Cx43 gap junctions mediate directional LDs trafficking from tumor cells to CAFs, restricting intracellular lipid energy pools sustaining malignant metabolic demands. Simultaneous blockade of glycolysis, mitochondrial respiration and lipid metabolism induces profound tumor‐cell metabolic collapse. The resulting metabolic stress strongly amplifies antitumor immunity and markedly suppresses both subcutaneous and orthotopic MOC1 tumors. Overall, this study establishes a gap‐junction‐driven triple metabolic starvation paradigm and offers mechanistic insights for next‐generation metabolic immunotherapies.