Targeting Amino Acid Metabolism

Metabolic dysregulation including amino acid synthesis and catabolism leads to profound changes both within cells and the tumor microenvironment (TME). Tumor cells have a high demand for almost all nutrients, including lipids and amino acids in the TME, leading to a lack of sufficient nutrition for other cells. Undoubtedly, amino acids are important nutrients for both tumor and immune cells. Tumor cells compete for extracellular resources, limit the amino acid supply to immune cells, and inhibit immune cell functions as a means to evade the immune system. Tumor cells use amino acids not only for their proliferation and invasion but also to enable tumor immune evasion. Moreover, T cells heavily rely on amino acid transportation and metabolism for their activation, differentiation, and function.

Amino Acid Metabolism in TME

A large body of work has demonstrated the diverse and important roles of amino acids in cancer metabolism.

• Glutamine

Glutamine is considered a critical amino acid for cancer cell metabolism as well as for rapidly dividing T cells. The increased metabolic demands of tumor cells and activated T lymphocytes may introduce competition for glutamine within the TME. This scenario would both promote proliferation and survival of tumor cells and simultaneously limit the capacity for T cell-mediated antitumor immunity. Glutamine within TME can also be active in rescheduling macrophages polarization toward the malignant M2 phenotype and enhancing cancer aggressiveness.

• Tryptophan

Local depletion of tryptophan by cancer cells and macrophages, through uptake and catabolism, suppresses antigen-specific T cell responses. Two different enzymes, indoleamine-2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO), catalyze the conversion of tryptophan into kynurenine. Kynurenine induces immunosuppression by binding to and activating the transcription factor aryl hydrocarbon receptor (AhR). Tryptophan depletion and kynurenine accumulation induce the formation of Tregs, leading to tumor growth.

• Arginine

Arginine metabolism is one of the mechanisms responsible for tumor progression. Many cancer cells are "addicted" to external arginine. Arginine metabolism impacts not only malignant cells but also the surrounding immune cells behavior, modulating growth, survival, and immunosurveillance mechanisms. Increasing evidence shows that arginine deprivation induces autonomous cancer cell death and enhances immune response.

Targeting Amino Acid Metabolism

Targeting amino acid metabolism is an attractive form of therapy, and interfering with amino acid availability can be selectively lethal to tumor cells. Targeting amino acid metabolic enzymes in cancer therapy is a promising strategy for the development of novel therapeutic agents. The most common amino acid-depletion strategies include depletion of asparagine with asparaginase, arginine with arginase, or arginine deiminase, glutamate with glutaminase inhibitors, and cysteine with cysteinase.

Many efforts have been devoted to developing therapeutic agents targeting amino acid transport and catabolic/biosynthetic pathways. Tryptophan catabolism has been in the spotlight for cancer immunotherapy. Multiple IDO1 inhibitors have been actively evaluated in clinical trials. Arginine deprivation is becoming a novel and promising clinical strategy for metabolism-based cancer therapy. Currently, arginine methyltransferases (PRMTs) inhibition is a promising and effective therapeutic strategy.