ABSTRACT Arginine is critical in biosynthesis, energy generation, cell proliferation, and immune regulation. In the tumor microenvironment (TME), due to limited supply and high consumption, the competition for arginine is extremely fierce. It always ends up with the victory of tumor cells and immunosuppressive cells, which leads to the arginine deficiency for anti‐tumor immune cells, resulting in immune tolerance of tumors. Therapies based on arginine metabolism have been extensively studied. An arginine deprivation therapy has been developed as the tumor progression relies on arginine support. To reverse the arginine shortage of anti‐tumor immune cells in TME, supplying arginine to enhance immune therapy has been proposed. Achieving the optimal antitumor effects of these two opposed therapies requires a better understanding of arginine metabolism in TME. In this review, we compared the transport, synthesis, and metabolism of arginine in tumor cells and various immune cells, and proposed key processes that may serve as potential therapeutic targets. In addition, for the two therapies for arginine, deprivation and supplementation, the recent research of them was discussed, and the relevant clinical trials were collected and summarized, which might provide reliable references for the further study and application of arginine‐based therapies.
Zhang et al. (2025) studied this question.