Glutamine metabolism and its roles in tumor radiotherapy by regulating DNA damage repair.

Background: As a conditionally essential amino acid that is required by tumor cells, glutamine serves as a key metabolic hub in tumor cells, functioning both as a carbon source for the tricarboxylic acid cycle and lipid synthesis and as a nitrogen source for amino acid and nucleotide biosynthesis. Cancer cells reprogram glutamine metabolism to enhance its uptake and utilization, thereby supporting anabolic demands, maintaining redox homeostasis, and ensuring genomic stability. The efficacy of radiotherapy against malignancies largely depends on tumor cell radiosensitivity, which is influenced by DNA damage repair capacity, microenvironmental hypoxia, and cancer stem cells. Growing evidence indicates that glutamine metabolism significantly modulates tumor radiosensitivity by regulating the supply of key substrates for DNA damage repair, affecting repair protein function through post-translational modifications, and altering chromatin architecture. Methods: We performed a comprehensive literature search across PubMed and Web of Science, focusing on studies investigating the interplay among glutamine metabolism, DNA damage response, and tumor radiosensitivity. Based on critical analysis and synthesis of the retrieved literature, we propose an integrated framework linking metabolic rewiring to DNA repair modulation in the context of radiotherapy. Results: This review identifies three principal mechanisms by which glutamine metabolism may regulate the DNA damage response in tumors: (1) supplying essential substrates for DNA repair, including purines and pyrimidines derived from glutamine-dependent biosynthesis; (2) modulating the activity and function of DNA repair proteins through O-GlcNAcylation and PARylation as critical post-translational modifications, as well as regulating chromatin accessibility via histone modifications; and (3) maintaining redox homeostasis and counteracting iron-dependent lipid peroxidation to modulate ferroptosis susceptibility following irradiation. Notably, targeted inhibition of glutamine metabolism significantly enhances tumor radiosensitivity and suppresses tumor growth, demonstrating the therapeutic potential of metabolic intervention. Conclusion: Glutamine metabolism plays a multifaceted role in regulating the DNA damage response and tumor radiosensitivity. Targeting glutamine metabolic pathways, particularly through substrate supply deprivation, post-translational modification interference, or chromatin remodeling modulation, may represent a rational strategy for radiosensitization. This review provides a theoretical basis for the development of novel combination regimens integrating glutamine metabolism inhibitors with radiotherapy.