ArticleProceedings of the National Academy of Sciences of the United States of America2019
Cystine-glutamate antiporter xCT deficiency suppresses tumor growth while preserving antitumor immunity.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 105 papers.
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Who cites it
105 citing papers in PubMed, 169 citations in OpenAlex.
- Pharmacological targeting of ferroptosis in cancer: mechanisms, tumor immunity, and translational challenges.Pharmacological reports : PR · 2026Review
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- Mechanistic insights into ferroptosis in thyroid cancer and its therapeutic implications.Apoptosis : an international journal on programmed cell death · 2026Review
- Overview of glutamine metabolism in stromal components of the tumor microenvironment and potential anti-tumor therapies.Genes & diseases · 2026Review
- Targeting ferroptosis in cancer: from mechanistic insights to therapeutic approaches.Molecular biomedicine · 2026Review
- Deciphering the MYCN-driven metabolic microenvironment of neuroblastoma.Trends in molecular medicine · 2026Review
- The critical role of ferroptosis in thyroid cancer development and potential therapeutic implications.Frontiers in oncology · 2026Review
- Ferroptosis in biliary tract cancer: Molecular mechanisms and therapeutic applications (Review).International journal of oncology · 2026Review
- Exploring Emerging Therapeutic Targets in Osteosarcoma by Revisiting the Immune and Cancer-Intrinsic Hallmarks of Cancer.Cancers · 2025Review
- Anti-Tumoral Treatment with Thioredoxin Reductase 1 Inhibitor Auranofin Fosters Regulatory T Cell and B16F10 Expansion in Mice.Antioxidants (Basel, Switzerland) · 2025Article
- Therapeutic targeting of cell death-immune crosstalk in cancer to rewire the tumor immune microenvironment.Molecular cancer · 2025Review
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- Prospects for ferroptosis therapies in cancer.Nature cancer · 2025Review
- Immunometabolic Targets in CD8Liver cancer · 2025Review
- Exploring Immune-Related Ferroptosis Genes in Thyroid Cancer: A Comprehensive Analysis.Biomedicines · 2025Article
- Pan-cancer analysis predicts MBOAT2 as a potential new ferroptosis related gene immune checkpoint.Discover oncology · 2025Article
- From mechanisms to medicine: Ferroptosis as a Therapeutic target in liver disorders.Cell communication and signaling : CCS · 2025Review
- The impact of metabolic reprogramming in hepatocellular carcinoma on T cell.Frontiers in immunology · 2025Review
- Regulation of dendritic cell biology by amino acids and their transporters.Frontiers in immunology · 2025Review
45 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
No grant is acknowledged in the PubMed record.
Abstract
T cell-invigorating cancer immunotherapies have near-curative potential. However, their clinical benefit is currently limited, as only a fraction of patients respond, suggesting that these regimens may benefit from combination with tumor-targeting treatments. As oncogenic progression is accompanied by alterations in metabolic pathways, tumors often become heavily reliant on antioxidant machinery and may be susceptible to increases in oxidative stress. The cystine-glutamate antiporter xCT is frequently overexpressed in cancer and fuels the production of the antioxidant glutathione; thus, tumors prone to redox stress may be selectively vulnerable to xCT disruption. However, systemic inhibition of xCT may compromise antitumor immunity, as xCT is implicated in supporting antigen-induced T cell proliferation. Therefore, we utilized immune-competent murine tumor models to investigate whether cancer cell expression of xCT was required for tumor growth in vivo and if deletion of host xCT impacted antitumor immune responses. Deletion of xCT in tumor cells led to defective cystine uptake, accumulation of reactive oxygen species, and impaired tumor growth, supporting a cancer cell-autonomous role for xCT. In contrast, we observed that, although T cell proliferation in culture was exquisitely dependent on xCT expression, xCT was dispensable for T cell proliferation in vivo and for the generation of primary and memory immune responses to tumors. These findings prompted the combination of tumor cell xCT deletion with the immunotherapeutic agent anti-CTLA-4, which dramatically increased the frequency and durability of antitumor responses. Together, these results identify a metabolic vulnerability specific to tumors and demonstrate that xCT disruption can expand the efficacy of anticancer immunotherapies.
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