Mechanistic target of rapamycin complex (mTORC)-glutamine axis in cancer: Mechanistic crosstalk, therapeutic resistance, and clinical opportunities

Cancer cells undergo metabolic reprogramming to support proliferation, survival, and adaptation to environmental stress. Among the nutrients that contribute to these processes, glutamine serves as a source of carbon and nitrogen for biosynthesis, energy production, redox regulation, and replenishment of tricarboxylic acid cycle intermediates. The mechanistic target of rapamycin complexes (mTORC1 and mTORC2) are regulators of cellular metabolism that integrate nutrient availability, growth factor signaling, and stress responses. Increasing evidence indicates that reciprocal interactions between mTOR signaling and glutamine metabolism may contribute to tumor progression and therapeutic adaptation. In this review, we examine the relationship between glutamine metabolism and mTOR signaling in cancer. We summarize current evidence supporting the role of mTORC1 in regulating glutamine uptake, utilization, anaplerosis, and biosynthetic metabolism, while highlighting that the contribution of mTORC2 to glutamine metabolism appears more indirect and remains less well defined. We further discuss the interaction of the mTORC-glutamine axis with oncogenic pathways, including MYC and phosphoinositide 3-kinase ( PI3K )/ protein kinase B ( AKT ) signaling, as well as tumor suppressor pathways (e.g., p53), and its potential role in therapeutic resistance. Finally, we discuss three emerging translational dimensions associated with the mTORC-glutamine axis: intracellular adaptation through autophagy and redox regulation, tumor-immune metabolic interactions, and dynamic metabolic biomarkers that may influence therapeutic responses. These dimensions are presented as related but distinct phenomena rather than components of a unified mechanistic model. Collectively, the available evidence indicates that glutamine metabolism and mTOR signaling form a context-dependent regulatory network that supports metabolic flexibility in cancer cells. Tumors exhibiting strong coupling between glutamine utilization and mTOR activity are particularly promising candidates for metabolic intervention, yet substantial heterogeneity exists across tumor types and genetic backgrounds. Current findings further suggest that successful therapeutic targeting of the mTORC-glutamine axis will likely require biomarker-guided patient stratification and rational combination strategies designed to overcome adaptive metabolic rewiring and treatment resistance.