TITLE:
The Role of L-Arginine in Digestive System Cancers: From Metabolism to Therapy
AUTHORS:
Hongmei Wu, Yan Qin, Linfeng Mo, Lishan Tang, Yan Chen, Shuya Ye, Wenyan Hong
KEYWORDS:
L-Arginine, Digestive System Malignancies, Metabolic Reprogramming, SLC Transporters, Arginine Deprivation Therapy, Biomarkers
JOURNAL NAME:
Journal of Biosciences and Medicines,
Vol.14 No.9,
September
8,
2026
ABSTRACT: L-arginine metabolic reprogramming is a critical metabolic hallmark of digestive system malignancies, exerting dual roles in tumorigenesis and disease progression through intricate regulatory networks. This review systematically summarizes recent advances in the L-arginine metabolic axis within digestive system tumors. It covers key steps along this axis, including transmembrane transport mediated by the Solute Carrier (SLC) family, intracellular flux partitioning through the arginase (ARG) and nitric oxide synthase (NOS) pathways, and downstream polyamine biosynthesis. Particular emphasis is placed on gastric cancer (GC), colorectal cancer (CRC), and hepatocellular carcinoma (HCC). Pancreatic cancer is also preliminarily discussed. Our synthesis reveals tissue-specific arginine metabolic profiles across different digestive system tumors. In GC, systemic disturbances in arginine-derived metabolites are observed. CRC exhibits a high dependency on exogenous arginine uptake mediated by SLC3A2. HCC displays aberrant arginine accumulation, and the non-enzymatic functions of metabolic enzymes further contribute to tumor promotion in this context. Furthermore, this review elucidates that L-arginine, acting through upstream signaling nodes of the mTORC1 pathway, exerts bidirectional regulatory effects on both tumor growth promotion and antitumor immune response modulation. Metabolic imbalance not only promotes tumor progression via epigenetic modifications but also remodels the immune microenvironment to facilitate immune evasion. In light of this regulatory network, arginine deprivation therapy, arginase inhibitors, and immuno-metabolic combination strategies have emerged as promising therapeutic avenues. Nevertheless, tumor heterogeneity, compensatory metabolic activation, and the complexity of metabolic-immune crosstalk pose substantial challenges to clinical translation. To date, arginine-targeted strategies have not been established as standard-of-care regimens in digestive system malignancies. The majority of evidence derives from preclinical models and early-phase exploratory trials, and thus their efficacy and safety await validation in large-scale studies. Looking forward, the integration of multi-omics technologies, gene editing, and organoid models may offer a viable roadmap for advancing clinical translation. Such biomarker-guided, personalized combination regimens could facilitate the implementation of L-arginine metabolism-targeted therapies in precision oncology for digestive system malignancies.