# Molecular mechanisms and therapies for tumor inhibition through the arginine metabolism pathway

## TL;DR

This review explores how arginine metabolism influences tumor growth and how targeting this pathway can lead to new cancer therapies.

## Contribution

The paper provides a comprehensive analysis of molecular mechanisms and therapeutic strategies targeting arginine metabolism in cancer.

## Key findings

- Arginine deprivation therapy has limited efficacy due to tumor resistance and metabolic reprogramming.
- New molecules targeting arginine metabolism show promise in inhibiting cancer cell growth.
- Combination therapies targeting arginine pathways enhance T cell activity against tumors.

## Abstract

Tumors are one of the major diseases leading to human death. Arginine metabolism plays an important role in tumor occurrence and metastasis. Based on the levels of arginine in tumor cells, methods such as recombinant arginine deiminase are used to reduce arginine in order to inhibit tumor growth. However, arginine deprivation therapy has limited efficacy in tumor cells due to increased arginine synthesis, resistance to chemotherapeutic agents, metabolic reprogramming, and the suppression of immune cells in the tumor microenvironment. Meanwhile, with the revelation of many new molecular mechanisms by which arginine controls tumor cell growth, numerous newly designed molecules targeting arginine metabolic pathways for cancer treatment have emerged. In this review, we integrate and analyze the responses of tumor cells and immune cells such as T cells to arginine and strategies for cancer therapy. At the molecular level, we review and discuss the mechanisms of specifically blocking arginine-regulated metabolic reprogramming in cancer cells, the effector factors from pathogenic microorganisms and metabolites from plants in inhibiting cancer cells via arginine metabolism, and arginine tRNA metabolic pathway. Finally, we discuss the mechanisms and case studies of using antineoplastic agents that target arginine metabolic pathways in combination. This review collects and integrates the mechanisms and experiences of treating various cancers through arginine and its metabolic derivatives, providing direct therapy guidance for cancer patients with disordered arginine metabolism in the tumor and immune cells.

L-Arg, L-Arginine; CAT, Cationic amino acid transporter; ARG1, Arginase 1; ODC, Ornithine decarboxylase; PAs, Polyamines; ADI, Arginine Deiminase; ASS1, Argininosuccinate synthase 1; ASL, Argininosuccinate lyase; GCN2, General control non-derepressible 2; mTORC1, mammalian Target Of Rapamycin Complex 1.Diagram illustrating key mechanisms targeting arginine metabolism in tumor and T cells, promoting T cell activity against tumors. It involves pathways like polyamine metabolism, endoplasmic reticulum stress response, and protein synthesis affected by arginine depletion. Key components include L-Arginine, ADI-PEG20, KEAP1 mutation, ribosome stalling, and translational control through pathways such as mTORC1 and GCN2. The diagram also shows drug interactions, cellular mutations, and the impact of exogenous factors on cancer cell resistance and death.

L-Arg, L-Arginine; CAT, Cationic amino acid transporter; ARG1, Arginase 1; ODC, Ornithine decarboxylase; PAs, Polyamines; ADI, Arginine Deiminase; ASS1, Argininosuccinate synthase 1; ASL, Argininosuccinate lyase; GCN2, General control non-derepressible 2; mTORC1, mammalian Target Of Rapamycin Complex 1.