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

Abstract

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.

Keywords: Cancer metabolism; Cancer treatment; Metabolic reprogramming; Tumor immunogenicity; Urea cycle.

Fig. 1

Overview of the urea cycle. The urea cycle (UC) represents the principal biochemical pathway for nitrogen excretion. This process is initiated within the mitochondrial matrix, where carbamoyl phosphate synthetase I (CPS1) facilitates the synthesis of carbamoyl phosphate (CP) from ammonia, carbon dioxide, and water. Subsequently, ornithine transcarbamylase (OTC) catalyzes the conversion of CP and ornithine into citrulline, which is then translocated to the cytoplasm. Within the cytoplasmic compartment, argininosuccinate synthetase (ASS1) incorporates an additional nitrogen atom from aspartate to synthesize argininosuccinate. The enzyme argininosuccinate lyase (ASL) then cleaves argininosuccinate to yield fumarate and arginine. Finally, arginase (ARG) hydrolyzes arginine to generate urea and regenerate ornithine, thereby completing the cycle

Fig. 2

Effect of dysregulation of the urea cycle on tumor immunogenicity. The dysregulation of the urea cycle (UCD) within the tumor microenvironment (TME) significantly impacts immune responses and facilitates immune evasion. (A) The accumulation of ammonia, resulting from impaired nitrogen metabolism, diminishes the efficiency of antigen presentation, thereby weakening immune surveillance. (B) Alterations in the expression of urea cycle enzymes, such as CPS1, OTC, and ARG1, affect MDM2 activity and arginine metabolism, further modulating immune responses. (C) The inhibition of immune checkpoints is intensified as dysregulated nitrogen metabolism enhances PD-L1 and CTLA-4 mediated T cell suppression, thereby promoting immune escape. Collectively, these metabolic alterations contribute to tumor progression by fostering an immunosuppressive microenvironment

Fig. 3

Targeting the Urea Cycle for Cancer Therapy

Fig. 4

Arginine Deprivation and ASS1 Re-expression in Tumor Resistance. Modulating arginine metabolism elicits varied responses in tumors. Arginine-depleting agents, such as ADI-PEG20 and PEG-rhARG1, cause arginine deprivation in tumors deficient in argininosuccinate synthetase 1 (ASS1), leading to metabolic stress, activation of autophagy, and subsequent tumor cell death in susceptible tumors. Conversely, resistant tumors may re-express ASS1 via MYC-mediated promoter demethylation, thereby facilitating the biosynthesis of arginine from citrulline and ammonia

Fig. 5

Polyamines in Cellular and Immune Functions. Polyamines (putrescine, spermidine, spermine) regulate gene expression, RNA structure, protein synthesis, and cell proliferation. They influence autophagy via EP300 and support the hyphenation of eIF5A. In the immune system, polyamines modulate dendritic cell (DC) and macrophage (MΦ) polarization, increasing TGF-β, IDO1, and ARG1 expression