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

Abstract

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 tumor-killing 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.

Water Evaporation-Driven Arginine Enantiomer Recognition on a Self-Powered Flexible Chip with High Specificity

“…As a proof of concept for enantiomer recognition, l -/ d -Arg was used as the target analyte to evaluate the chiral-sensing performance of the self-powered chip and elucidate its mechanism. Arg is necessary for cell division, brain chemistry, immune responses, blood vessel dilation, and neurotransmission d -Arg has significant pharmacological activities in mammals …”

Beneficial effects of L-Arginine in patients hospitalized for COVID-19: New insights from a randomized clinical trial

“…Further studies, ideally exploring more cytokines and chemokines, are warranted to dissect how exactly L-Arginine is able to modulate their circulating levels. Potential mechanisms by which L-Arginine exerts anti-inflammatory effects may include the reconstitution of circulating L-Arginine levels, a correction of nitric oxide dysfunction, and/or a direct action on immune cells [38] , [39] , [40] , [41] , [42] , [43] , [44] , [45] .…”

Nanotechnology Reprogramming Metabolism for Enhanced Tumor Immunotherapy

“…163 Similarly, Zhang et al reported a multivesicular liposome capable of both supplying L-arginine to the acidic TME and blocking cationic amino acid transporter 2 (CAT-2) with shRNA, which increased the amount of tumor infiltrating CD8 + T cells and sensitized ICB therapy with anti-PD-L1. 164 Targeting key enzymes in the metabolic pathways of various nutrients is a more common strategy to inhibit endogenous nutrient consumption. The diversity and plasticity of nanotechnologies allow such goals to be achieved at protein or gene levels.…”