<p>Ammonia has long been regarded as the end-toxic product of hepatic metabolism. Under normal physiological conditions, ammonia is metabolized through the urea cycle; however, its metabolic imbalance is closely related to various diseases, including hepatic encephalopathy, liver fibrosis, and cancer. Ammonia-induced cell death, specifically the selective death of immune cells, has emerged in recent years as a new form of cell death in the field of tumor biology, offering a new perspective on the regulation of tumor cell fate. This review creatively focuses on the role of ammonia in tumorigenesis, development, and treatment resistance. We systematically reviewed the sources and dynamic balance of ammonia in the tumor microenvironment and found that it plays a key role in tumor metabolic reprogramming by regulating glutamine metabolism, mitochondrial function, and lysosomal stability in tumor cells. Ammonia can also induce the selective death of immune cells, reshape the immune cell map in the tumor microenvironment, and regulate the anti-tumor immune response. Mechanistically, we analyzed the multi-level network of ammonia metabolism regulation, including the role of glutamine synthetase, the mTOR signaling pathway, and epigenetic modification in ammonia death. In addition, this review emphasizes the importance of ammonia as a potential target for cancer therapy and proposes multimodal strategies combining metabolic regulation and immunotherapy to achieve precision in cancer treatment. Finally, the comprehensive map of ammonia in the tumor ecosystem was constructed, highlighting its potential clinical value as a new anti-cancer target.</p> Graphical Abstract <p>Ammonia: a new paradigm for cancer treatment. Ammonia has long been recognized as the final toxic metabolite of hepatic nitrogen disposal, predominantly cleared via the urea cycle under physiological conditions. Recent evidence highlights its dysregulation as a critical factor in tumor initiation, progression, and immune evasion. This review systematically summarizes the sources of ammonia in tumor cells and its key role in tumor metabolic reprogramming by regulating glutamine metabolism, mitochondrial function, and lysosomal stability within tumor cells. Ammonia-induced cell death involves multiple immune effector cells, which suppress the anti-tumor response of the immune system through multiple immune regulatory mechanisms. An in-depth analysis was conducted on the multi-level network of ammonia metabolism regulation, including key enzymes, signaling pathways, and epigenetic mechanisms, providing novel therapeutic ideas for targeting ammonia metabolism. Based on these findings, this study emphasizes the importance of ammonia as a potential target for tumor therapy and proposes a multimodal strategy that combines ammonia metabolism regulation with immunotherapy, which is expected to open new frontiers in precision medicine for tumors. Made by Figdraw.</p> <p></p>