L-ARGININE METABOLISM IN CANCER: LINKING TUMOR INFLAMMATION, APOPTOSIS, AND ANGIOGENESIS

Abstract

L-arginine metabolism has emerged as a central regulatory axis in cancer biology, integrating metabolic reprogramming, immune modulation, and tumor microenvironment remodeling. Cancer cells frequently rewire arginine uptake, synthesis, and degradation pathways to sustain proliferation, evade immune surveillance, and adapt to metabolic stress conditions. This metabolic flexibility is enabled through coordinated regulation of key enzymatic nodes, including argininosuccinate synthase 1, argininosuccinate lyase, arginase isoforms (ARG1 and ARG2), and nitric oxide synthases, which collectively control intracellular arginine availability and its downstream signaling outputs. In the tumor microenvironment, arginine metabolism becomes a competitive interface between malignant cells and immune populations. Tumors exploit arginine depletion through increased arginase activity in myeloid-derived suppressor cells and tumor-associated macrophages, leading to impaired T-cell activation and suppression of anti-tumor immunity. In parallel, nitric oxide generated from arginine metabolism exerts concentration-dependent effects that can either promote tumor progression through angiogenesis and survival signaling or induce cytotoxic stress and apoptosis at higher levels. Additionally, polyamine biosynthesis derived from arginine catabolism further supports tumor growth, chromatin remodeling, and resistance to cell death. This review provides a comprehensive synthesis of L-arginine metabolic pathways in cancer, with a particular focus on their roles in tumor-associated inflammation, apoptotic regulation, and angiogenesis. We also discuss therapeutic strategies targeting arginine dependency, including arginine deprivation therapies, arginase inhibition approaches, and emerging combination immunometabolic strategies, as well as key resistance mechanisms such as argininosuccinate synthase 1 re-expression and metabolic rewiring. Collectively, L-arginine metabolism represents a multifunctional metabolic hub that connects tumor progression with immune regulation and offers multiple promising therapeutic entry points in oncology.