SREBP-1 increases glucose uptake to promote tumor resistance to lysosome inhibition.

Lysosomes are critical for maintaining cellular homeostasis and nutrient availability, yet how tumor cells survive under lysosomal inhibition remains unclear. Here, we revealed that inhibiting lysosome function with chloroquine unexpectedly stimulated glucose uptake across various cancer cells. This effect was driven by sterol regulatory element-binding protein 1 (SREBP-1), a key lipogenic transcription factor, which specifically increased the expression of glucose transporters GLUT3 and GLUT6, enhancing glucose uptake and macromolecule synthesis. Elevated glucose, induced by chloroquine, stabilized SREBP cleavage-activating protein (SCAP), the activator of SREBP-1, further amplifying its activity and contributing to tumor resistance to lysosome inhibition. Disrupting this SREBP-1-glucose uptake feedforward loop by combining chloroquine with inhibitors of glucose transporters, SREBP-1, or lipogenic enzymes induced a synergistic antitumor effect in squamous cell and adenocarcinoma lung cancer patient-derived organoids and xenografts. This combination impaired mitochondrial structure and function, inducing apoptotic tumor cell death. Our study uncovers a role for SREBP-1 in regulating glucose metabolism and provides a promising therapeutic strategy that combines lysosome inhibition with glucose transporter or lipogenic enzyme inhibition for effective cancer treatment.