The role of L-Arginine metabolism in the hallmarks of cancer as an emerging pathway to drug design

Cancer remains a leading cause of mortality worldwide and continues to challenge therapy due to its biological complexity and metabolic plasticity. Among the pathways supporting malignant progression, L-arginine metabolism has emerged as a key regulator of tumor cell fitness, integrating nutrient sensing, bioenergetics, redox balance, and immune modulation. In cancer, arginine homeostasis is frequently rewired, generating L-arginine auxotrophy and increased dependence on extracellular L-arginine, which contributes to several hallmarks of cancer, including proliferation, metabolic adaptation, angiogenesis, immune evasion, and tumor aggressiveness. This review discusses the molecular mechanisms through which L-arginine metabolism reshapes tumor biology, focusing on signaling pathways such as mTORC1 and on tumor-immune interactions within the tumor microenvironment. Therapeutic strategies targeting this pathway, including L-arginine deprivation therapies and emerging small-molecule modulators, are also examined alongside adaptive resistance mechanisms that may limit their clinical efficacy.