Urea cycle dysregulation: a new frontier in cancer metabolism and immune evasion

Cancer cells experience metabolic reprogramming to enhance the synthesis of nitrogen and carbon, facilitating the production of macromolecules essential for tumor proliferation and growth. A central strategy in this process involves reducing catabolic activities and managing nitrogen, thereby improving the efficiency of nitrogen utilization. The urea cycle (UC), conventionally recognized for its role in detoxifying excess nitrogen in the liver, is pivotal in this metabolic transition. Beyond the hepatic environment, the differential expression of UC enzymes facilitates the utilization of nitrogen for the synthesis of metabolic intermediates, thereby addressing the cellular metabolic requirements, especially under conditions of nutrient scarcity. In oncogenic contexts, the expression and regulation of UC enzymes undergo substantial modification, promoting metabolic reprogramming to optimize nitrogen assimilation into cellular biomass. This reconfigured UC not only enhances tumor cell survival but also plays a pivotal role in the reorganization of the tumor microenvironment (TME), thereby aiding in immune evasion. This review examines the mechanistic underpinnings of urea cycle dysregulation (UCD) in cancer, highlighting its dynamic roles across various tumor types and stages, as well as the therapeutic implications of these alterations. Understanding how UC relaxation promotes metabolic flexibility and immune evasion may help develop novel therapeutic strategies that target tumor metabolism and enhance anti-cancer immunity.