Targeting Arginine Metabolism to Reverse Immune Paralysis in Cancer

The immune system plays an essential role in protecting the host from malignant transformation through immune surveillance, a concept that was later expanded by the cancer immunoediting framework. While immune responses eliminate emerging tumors, they can also impose selective pressure that promotes tumor adaptation and immune escape. Among the mechanisms involved in this process, metabolic immune suppression has gained increasing attention, as it weakens immune function without causing immune cell death. In this context, the semi-essential amino acid L-arginine has emerged as an important metabolic factor regulating immune competence within the tumor microenvironment. The availability of arginine directly affects immune cell activation, proliferation, and effector function, acting as a metabolic checkpoint rather than only as a biosynthetic substrate. Tumors actively generate arginine-poor niches through the expression of arginine- metabolizing enzymes in tumor cells as well as in immunosuppressive myeloid and stromal populations. As a result, immune cells, particularly T lymphocytes, undergo a reversible state of functional paralysis characterized by preserved viability but impaired cell-cycle progression, reduced protein synthesis, and weakened effector responses. In contrast, tumor cells often tolerate or adapt to low arginine levels, leading to a metabolic imbalance that selectively suppresses antitumor immunity. In this review, we summarize current knowledge on arginine- dependent immune suppression, focusing on arginase- and nitric oxide synthase-mediated pathways, competition for arginine transport, and nutrient-sensing signaling through mTORC1 and GCN2. We also discuss the evolutionary conservation and reversibility of this mechanism and its interplay with other immunosuppressive metabolic pathways. Finally, we highlight therapeutic strategies targeting arginine metabolism, emphasizing the arginine system as a key regulator of tumor-induced immune suppression and a potential target for cancer immunotherapy.