ArticleCancer research2015
l-Arginine depletion blunts antitumor T-cell responses by inducing myeloid-derived suppressor cells.
Article in Cancer research, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 190 papers.
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Who cites it
190 citing papers in PubMed, 260 citations in OpenAlex.
- Myeloid-derived suppressor cells in cancer: biology, regulatory networks and theranostic prospects.Signal transduction and targeted therapy · 2026Review
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- Serum metabolomics profiling in head and neck squamous cell carcinoma: a multicentre diagnostic study.EBioMedicine · 2026Article
- Arginine Deprivation of ASS1-Deficient Cancers Drives Mistranslation and Shared Neoepitope Production.Cancer research · 2026Article
- Immunometabolic Stress and Immune Suppression in Clear-Cell Renal Cell Carcinoma: Perspectives in Therapeutic Strategy.International journal of molecular sciences · 2026Review
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- Systemic multi-omics analysis reveals interferon response heterogeneity and links lipid metabolism to immune alterations in severe COVID-19.Genome medicine · 2026Article
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- Pan-cancer biomarkers of immune therapy resistance: mechanisms and clinical translation.Frontiers in cell and developmental biology · 2026Review
- Advancing osteosarcoma treatment: the impact of intratumoral metabolic reprogramming on immunotherapy.Frontiers in immunology · 2026Review
- The role of notch signaling in tumor angiogenesis in hematological malignancies.Frontiers in oncology · 2026Review
- Molecular mechanisms and therapies for tumor inhibition through the arginine metabolism pathway.Frontiers in oncology · 2026Review
- Recent advances in dissolving microneedles for breast cancer immunotherapy: local delivery and tumor microenvironment remodeling.Frontiers in immunology · 2026Review
- The role of L-Arginine metabolism in the hallmarks of cancer as an emerging pathway to drug design.Frontiers in pharmacology · 2026Review
- Amino acid metabolic regulatory network in tumor immune escape: mechanistic exploration and intervention directions.Frontiers in immunology · 2026Review
- Drug resistance mechanisms of immunotherapy and translational strategies for reversing resistance for hepatocellular carcinoma: from bench to bedside.Frontiers in immunology · 2026Review
- Amino acids metabolism: a potential target for cancer treatment.Molecular cancer · 2025Review
- Immune checkpoint biology in hepatocellular carcinoma (Review).Oncology letters · 2025Review
130 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
Abstract
Enzymatic depletion of the nonessential amino acid l-Arginine (l-Arg) in patients with cancer by the administration of a pegylated form of the catabolic enzyme arginase I (peg-Arg I) has shown some promise as a therapeutic approach. However, l-Arg deprivation also suppresses T-cell responses in tumors. In this study, we sought to reconcile these observations by conducting a detailed analysis of the effects of peg-Arg I on normal T cells. Strikingly, we found that peg-Arg I blocked proliferation and cell-cycle progression in normal activated T cells without triggering apoptosis or blunting T-cell activation. These effects were associated with an inhibition of aerobic glycolysis in activated T cells, but not with significant alterations in mitochondrial oxidative respiration, which thereby regulated survival of T cells exposed to peg-Arg I. Further mechanistic investigations showed that the addition of citrulline, a metabolic precursor for l-Arg, rescued the antiproliferative effects of peg-Arg I on T cells in vitro. Moreover, serum levels of citrulline increased after in vivo administration of peg-Arg I. In support of the hypothesis that peg-Arg I acted indirectly to block T-cell responses in vivo, peg-Arg I inhibited T-cell proliferation in mice by inducing accumulation of myeloid-derived suppressor cells (MDSC). MDSC induction by peg-Arg I occurred through the general control nonrepressed-2 eIF2α kinase. Moreover, we found that peg-Arg I enhanced the growth of tumors in mice in a manner that correlated with higher MDSC numbers. Taken together, our results highlight the risks of the l-Arg-depleting therapy for cancer treatment and suggest a need for cotargeting MDSC in such therapeutic settings.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.