Cancer-associated fibroblasts promote imatinib resistance in gastrointestinal stromal tumors through PGK1-mediated metabolic reprogramming

GISTs frequently develop imatinib resistance. The study uncovered that cancer-associated fibroblasts (CAFs) drive this resistance through the TGF-β1/CCN2/Rack1/PGK1 mechanism. Specifically, CAF-secreted TGF-β1 amplifies the CCN2/Rack1 axis, which activates PI3K/AKT signaling. This induces PGK1 phosphorylation, promoting metabolic reprogramming (enhanced glycolysis) that fuels tumor survival and drug resistance. Targeting CAF-GIST interactions is proposed as a therapeutic strategy.