Glutamine metabolic interaction network reshapes tumor immunotherapy resistance

Glutamine metabolism is often viewed as a cancer cell dependency, but its biological consequences depend on how glutamine and its carbon- and nitrogen-derived metabolites are used across malignant, immune, and stromal compartments. In this article, we introduce the glutamine metabolic interaction network (GMIN) as an analytical framework that integrates nutrient partitioning, competition, metabolic cooperation, and metabolite-mediated regulation while distinguishing candidate associations from functionally supported interactions. We review the biochemical, spatial, and treatment-dependent determinants of GMIN states, including emerging evidence for metabolic remodeling during immunotherapy resistance. Current clinical evidence neither supports uniform glutaminase 1 dependence nor establishes a single preferred strategy for glutamine-directed intervention. GMIN may therefore provide a framework for identifying context-specific glutamine-centered interactions and prioritizing them for state-resolved therapeutic targeting.