Arginine Supplementation Targeting Tumor-Killing Immune Cells Reconstructs the Tumor Microenvironment and Enhances the Antitumor Immune Response

The tumor microenvironment (TME) is characterized by several immunosuppressive factors, of which weak acidity and L-arginine (L-arg) deficiency are two common features. A weak acidic environment threatens the survival of immune cells, and insufficient L-arg will severely restrain the effect of antitumor immune responses, both of which affect the efficiency of cancer treatments (especially immunotherapy). Meanwhile, L-arg is essential for tumor progression. Thus, two strategies, L-arg supplementation and L-arg deprivation, are developed for cancer treatment. However, these strategies have the potential risk of promoting tumor growth and impairing immune responses, which might lead to a paradoxical therapeutic effect. It is optimal to limit the L-arg availability of tumor cells from the microenvironment while supplying L-arg for immune cells. In this study, we designed a multivesicular liposome technology to continuously supply alkaline L-arg, which simultaneously changed the acidity and L-arg deficiency in the TME, and by selectively knocking down the CAT-2 transporter, L-arg starvation of tumors was maintained while tumorkilling immune cells were enriched in the TME. The results showed that our strategy promoted the infiltration and activation of CD8+ T cells in tumor, increased the proportion of M1 macrophages, inhibited melanoma growth, and prolonged survival. In combination with anti-PD-1 antibody, our strategy reversed the low tumor response to immune checkpoint blockade therapy, showing a synergistic antitumor effect. Our work provided a reference for improving the TME combined with regulating nutritional competitiveness to achieve the sensitization of immunotherapy.