Rare-Earth-Coordinated Glutamine Nanostructure-Induced “Pseudo-Overnutrition” Metabolic Therapy

Abstract Tumor cells display a strong dependency on nutrients, yet nutrient-deprivation strategies often fail due to their metabolic plasticity and compensatory mechanisms, and can even promote invasion and metastasis. Here, we propose a metabolic therapeutic strategy that leverages rather than suppresses tumor nutrient addiction, termed “pseudo-overnutrition”. This approach induces tumor cells to continuously uptake nutrient analogs that cannot be effectively utilized, thereby decoupling nutrient input from nutrient utilization and triggering metabolic collapse. To validate this concept, we designed and assembled rare-earth–coordinated glutamine nanoparticles (RE-Gln). RE-Gln preferentially interacts with glutamine transporters on tumor-cell membranes, is subsequently internalized predominantly through macropinocytosis, and accumulates within lysosomes. The progressive accumulation of RE-Gln disrupts V-ATPase–dependent lysosomal nutrient sensing and blocks mTORC1 activation, rendering cells unable to effectively utilize nutrients despite continuous uptake. Importantly, the resulting dysfunction is confined primarily to lysosomes, while mitochondrial integrity remains preserved. This lysosome-centered impairment ultimately causes widespread disruption of glutamine and glucose metabolism. Moreover, the high-glutamine microenvironment induced by RE-Gln impairs lysosomal biogenesis and function in dendritic cells, enhancing antigen presentation and activating antitumor immunity. These findings establish “pseudo-overnutrition” as a previously unrecognized concept for metabolic intervention in cancer and provide a mechanistic framework for converting tumor nutrient dependency into a therapeutic vulnerability.