METTL7A Downregulation Drives SLC1A5-Mediated Glutamine Competition to Promote Tumor Proliferation and Suppress CD8⁺...

Tumor metabolic dysregulation is a critical determinant of tumor progression and response to immunotherapy. Aberrant glutamine metabolism is a hallmark of gastric cancer (GC). However, beyond fueling GC cell anabolism, its role in remodeling the immunosuppressive tumor microenvironment remains poorly understood. Here, we show that GC cells overexpress solute carrier family 1 member 5 (SLC1A5) to drive glutamine accumulation, which not only promotes their own proliferation but also reduces glutamine availability to CD8⁺ T cells, thereby suppressing antitumor immunity. These dual effects cooperatively drive GC progression. Mechanistically, loss of methyltransferase-like protein 7A (METTL7A) stabilizes SLC1A5 mRNA by reducing its m6A modification. Concurrently, METTL7A deficiency increased N-glycosyltransferase β-1,4-galactosyltransferase 5 (B4GALT5) expression. B4GALT5 stabilizes SLC1A5 via N-glycosylation at the N212 site, which blocks K48-linked polyubiquitination and proteasomal degradation. We identify the natural flavonoid luteolin as an agent that upregulates METTL7A expression, which subsequently downregulates SLC1A5 expression and inhibits GC progression. Furthermore, luteolin significantly enhances the efficacy of anti-PD-1 therapy in GC. Collectively, our findings reveal that SLC1A5-mediated glutamine competition drives both tumor cell proliferation and immune evasion in GC, and suggest that targeting the METTL7A/SLC1A5 axis may represent a promising therapeutic strategy.