18F-FDG-PET/CT-negative gastric cancer employs glutamine-based gluconeogenesis and fatty acid oxidation to support tumor growth.

Most tumors exhibit increased glucose uptake and reprogram metabolism to aerobic glycolysis to meet their demands for macromolecule biosynthesis and energy production. Consequently, PET/CT using 18F-2-fluoro-2-deoxy-D-glucose (18F-FDG-PET/CT) has been developed and is clinically utilized in cancer imaging diagnostics. However, numerous cancers demonstrate negative imaging during 18F-FDG-PET/CT detection, suggesting these cancers employ alternative metabolic rewiring. In this study, we discovered that 18F-FDG-PET/CT-negative gastric cancers coordinate glutamine-based gluconeogenesis and fatty acid oxidation to meet DNA and ATP demands, sustaining tumor growth despite low glucose uptake. PCK and CPT1A, the key enzymes which are responsible for remodeling the metabolism, were highly expressed in FDG-PET/CT-negative gastric cancers. Accordingly, PCK/CPT1A negatively correlated with 18F-FDG imaging levels and positively correlated with poorer clinical classifications. Mechanistically, PPARγ is highly expressed in FDG-PET/CT-negative cells and drives the transcription of the PCK and genes. Pharmacological inhibition of the PCK/CPT1A significantly suppressed tumor growth in 18F-FDG-PET/CT-negative gastric cancers, as demonstrated in both cell-derived xenograft (CDX) and patient-derived xenograft (PDX) models. Together, these results highlight the heterogeneity of tumor cells from metabolic perspective, and identify PCK/CPT1A as a target for metabolic reprogramming and precision therapy of 18F-FDG-PET/CT-negative cancers.