This study systematically elucidates the central regulatory function of glutaminase (GLS) genes in pan-cancer contexts and their role in remodeling the tumor immune microenvironment. Through the integration and analysis of extensive pan-cancer datasets, it was revealed that GLS expression exhibits a highly cancer-specific pattern and is associated with a “double-edged sword” prognostic value, reflecting the cancer type’s dependence on the “ammonia death” threshold effect. The primary innovation of this research lies in demonstrating that GLS influence genomic stability through metabolism-epigenetic cross-dialogue, thereby driving unique immune microenvironment regulation. Specifically, GLS promote immune recognition while simultaneously inducing excessive ammonia-induced “ammonia death” of CD8⁺ T cells, leading to immune exhaustion. This mechanism has been corroborated by multiple algorithms across various cancer types. This study has for the first time established a precise intervention framework based on GLS expression: Targeting and inhibiting the GLS activity of high-expression cancer types or activating the urea cycle detoxification pathway (CPS1) of low-expression cancer types can effectively enhance the immune response. The establishment of innovative serum ammonia metabolism markers and the ultimate confirmation of GLS as the core hub integrating the three dimensions of metabolism, genomics and immunity have laid a theoretical foundation for tumor synergistic therapy targeting ammonia metabolism.
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Li, X., Lu, S., Nie, Y., Fang, J., Gao, S., Qi, W., Li, K., Zhang, T., Sima, J. (2025) Research on the Expression Pattern, Prognostic Value, and Immune Microenvironment Regulatory Mechanism of GLS Gene in Pan-cancer. Journal of Disease and Public Health, 1(2), 42-63. https://doi.org/10.71052/jdph/CCKU7032