ArticleCancer cell2023
Enzyme-mediated depletion of methylthioadenosine restores T cell function in MTAP-deficient tumors and reverses immunotherapy resistance.
Article in Cancer cell, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
41 citing papers in PubMed, 49 citations in OpenAlex.
- Camrelizumab plus nimotuzumab as second-line therapy for advanced esophageal squamous cell carcinoma: a multicenter phase II study.Journal for immunotherapy of cancer · 2026Trial
- Phase 2 study of cabozantinib (XL184) with nivolumab and ipilimumab for the treatment of poorly differentiated neuroendocrine carcinomas (ETCTN10315).The oncologist · 2026Trial
- A gut microbiota rheostat forecasts responsiveness to PD-L1 and VEGF blockade in mesothelioma.Nature communications · 2024Trial
- Integrated Multiomic Profiling Enhances Risk Stratification and Prognostication in Canine Osteosarcoma.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Article
- Comprehensive Genomic and Transcriptomic Characterization of MTAP Loss across Advanced Solid Tumors.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Observational
- MTAP Deficiency as a Metabolic Vulnerability in Cancer: Implications for Synthetic Lethal Therapy.Cancer science · 2026Review
- Presenting features and outcomes to standard systemic therapies in patients with MTAP-deleted advanced non-small cell lung cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Article
- An immunogenomic classification of solid tumours reveals subtype-specific therapeutic vulnerabilities for immunotherapy.EBioMedicine · 2026Article
- The Evolving Landscape of Immune Regulation and Immunotherapy in Cholangiocarcinoma and Biliary Tract Cancer.Cancers · 2026Review
- Genomic landscape of pleural mesothelioma in Japanese patients: A comprehensive analysis using nationwide database.Translational oncology · 2026Article
- Targeting methionine-induced pyroptosis enhances anti-tumor immunity.Science China. Life sciences · 2026Article
- MTAP Deletion in Oncogenesis: A Synthetic Lethality Scenario.Cancer research · 2026Review
- Case Report: Targeting EGFR exon 20 insertion and MTAP loss in refractory metastatic upper tract urothelial carcinoma.Frontiers in oncology · 2026Article
- Review
- MTAP-Null Tumors: A Comprehensive Review on Synthetic Vulnerabilities and Therapeutic Strategies.Cells · 2025Review
- Exploring the role of 338 cerebrospinal fluid metabolites in primary brain malignancies risk: a Mendelian randomization study.Discover oncology · 2025Article
- MTA-Cooperative PRMT5 Inhibitors Are Efficacious in MTAP-Deleted Malignant Peripheral Nerve Sheath Tumor Models.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Article
- Resilience and Vulnerabilities of Tumor Cells under Purine Shortage Stress.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Article
- Unusual Morphologic Presentation of Perineural Spread From Cutaneous Squamous Cell Carcinoma: Diagnosis Aided by Comprehensive Molecular Analysis and Machine Learning.Journal of cutaneous pathology · 2025Article
- Interferon Epsilon Loss Is Elusive 9p21 Link to Immune-Cold Tumors, Resistant to Immune Checkpoint Therapy, and Endogenous CXCL9/10 Induction.Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer · 2025Review
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Authors and funding
21 authors at 9 institutions in 1 country.
Funding
Abstract
Chromosomal region 9p21 containing tumor suppressors CDKN2A/B and methylthioadenosine phosphorylase (MTAP) is one of the most frequent genetic deletions in cancer. 9p21 loss is correlated with reduced tumor-infiltrating lymphocytes (TILs) and resistance to immune checkpoint inhibitor (ICI) therapy. Previously thought to be caused by CDKN2A/B loss, we now show that it is loss of MTAP that leads to poor outcomes on ICI therapy and reduced TIL density. MTAP loss causes accumulation of methylthioadenosine (MTA) both intracellularly and extracellularly and profoundly impairs T cell function via the inhibition of protein arginine methyltransferase 5 (PRMT5) and by adenosine receptor agonism. Administration of MTA-depleting enzymes reverses this immunosuppressive effect, increasing TILs and drastically impairing tumor growth and importantly, synergizes well with ICI therapy. As several studies have shown ICI resistance in 9p21/MTAP null/low patients, we propose that MTA degrading therapeutics may have substantial therapeutic benefit in these patients by enhancing ICI effectiveness.
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