Glutamine synthetase: Spotlighting the emerging roles in tumor progression and therapeutic avenues

Glutamine synthetase (GS), a key enzyme in nitrogen metabolism, acts as a central node by catalyzing the synthesis of glutamine from glutamate and ammonia, playing a pivotal role in maintaining cellular metabolic homeostasis. Studies have shown that GS is upregulated in various types of tumors, and its expression level is closely associated with tumor initiation, progression, and poor prognosis. This review systematically explores the multifaceted molecular mechanisms through which GS promotes malignant tumor progression. Within the tumor microenvironment, GS enhances the immunosuppressive functions of regulatory T cells (Tregs) and M2-type tumor-associated macrophages (TAMs), thereby inducing immune escape. It also promotes abnormal tumor vasculature by reprogramming metabolism and regulating key cellular behaviors involved in angiogenesis. Furthermore, GS mediates resistance to L-asparaginase and radiotherapy. It also enhances tumor invasion and metastasis via mechanisms including epithelial-mesenchymal transition (EMT). Additionally, this article summarizes potential GS-targeted therapeutic strategies, including small-molecule inhibitors and nano-drug delivery systems, offering theoretical foundations and new directions for reversing tumor drug resistance and developing novel anti-tumor therapies. By comprehensively elucidating the role of GS in multiple malignant processes-including cell proliferation, angiogenesis, invasion and metastasis, immune evasion and therapy resistance-this review aims to provide new insights into precision therapies targeting tumor metabolic reprogramming.