Arginine metabolism, polyamine homeostasis and ferroptosis in cancer: Molecular links and therapeutic opportunities (Review).

Arginine metabolism, polyamine homeostasis and ferroptosis are interconnected molecular processes that influence tumor growth, immune remodeling and therapeutic responses. The availability of arginine is affected by tumor‑cell biosynthesis and uptake, myeloid arginase (ARG)‑mediated depletion, nitric oxide synthase (NOS)‑driven diversion and stromal‑vascular nutrient transport and microenvironmental remodeling. These input signals regulate the synthesis, uptake‑efflux cycling and catabolic turnover of polyamines, thereby creating an inhibitory buffering state or an oxidative state that can lower the ferroptosis threshold. Ferroptosis is controlled by the balance of lipid peroxidation triggers, including polyunsaturated fatty acid‑phospholipid load, iron‑dependent amplification and lipoxygenase activity, as well as buffering systems such as the cystine/glutamate antiporter system Xc-‑glutathione‑glutathione peroxidase 4 axis, ferroptosis suppressor protein 1‑coenzyme Q10, dihydroorotate dehydrogenase and GTP cyclohydrolase 1‑tetrahydrobiopterin (BH4). The immunological consequences of ferroptotic tumor‑cell death are context‑dependent, as dying cells may promote interferon‑gamma‑driven antitumor immunity or, conversely, reinforce myeloid‑mediated immunosuppression. The present review summarized the molecular links among arginine metabolism, polyamine homeostasis and ferroptosis in cancer and discusses therapeutic opportunities involving biomarker‑guided combinations targeting arginine, polyamine blockade, ferroptosis sensitization and immune checkpoint blockade.