ArticleJournal for immunotherapy of cancer2021
TGFβ drives NK cell metabolic dysfunction in human metastatic breast cancer.
Article in Journal for immunotherapy of cancer, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 95 papers.
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Who cites it
95 citing papers in PubMed, 138 citations in OpenAlex.
- Reconstitution of Natural Killer cells after allogeneic hematopoietic stem cell transplantation is facilitated by Huiyang-Guben decoction through activating the Smad7/Stat3 signal pathway.Molecular and cellular biochemistry · 2024Trial
- DRP1 depletion protects NK cells from hypoxia-induced dysfunction.Redox report : communications in free radical research · 2026Article
- Next-generation natural killer cell therapy: bench to bedside and beyond.Signal transduction and targeted therapy · 2026Review
- Advancing CAR-NK cell therapy in solid tumors: Current landscape and future directions.Cell reports. Medicine · 2026Review
- ITPKB is a conserved regulator of natural killer cell desensitization/education that constrains antitumor immunity.bioRxiv : the preprint server for biology · 2026Article
- CAR-NK cell therapy for hematological malignancies.Blood advances · 2026Review
- Glucose metabolic reprogramming as a driver of immunosuppression in the tumour microenvironment.Clinical and translational medicine · 2026Review
- Multiomics immune profiling of a patient-relevant orthotopic lung cancer model using SEPARATE-Seq.Nature communications · 2026Article
- SMAD7 drives natural killer cell antitumor activity through canonical TGF-β blockade and non-canonical transcriptional activation of STAT5A.Journal for immunotherapy of cancer · 2026Article
- Mitochondrial impairment and mTORC1 signalling exhaustion define NK Cell dysfunction progression in melanoma.Cancer immunology, immunotherapy : CII · 2026Article
- Review
- Endometriosis immune microenvironment timing shifts: from immune escape to immune exhaustion.Cell death discovery · 2026Review
- The application of nanotechnology in regulating mitochondrial function in tumor microenvironment for cancer therapy.Theranostics · 2026Review
- Mitochondrial Energy Metabolism in Cancer, Immunoregulation and Antitumour Response.Advances in experimental medicine and biology · 2026Review
- Mitochondrial dysfunction as a metabolic checkpoint of immunotherapy response in colorectal cancer.Frontiers in immunology · 2026Review
- Metabolic licensing and restriction of innate immunity in the tumor microenvironment.Frontiers in immunology · 2026Review
- Defining treatment-resistant brain cancer: Genetic screening to identify oncogene-driven immunomodulation and therapy resistance.Cancer gene therapy · 2026Review
- Triple-Negative Breast Cancer Cells Resist Natural Killer Cell-Mediated Killing Through Interleukin-11 Trans-Signaling.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- One-step knock-in CAR constructs in human NK cells enable scalable, TGFβ1-resistant immunotherapy for solid tumors.Theranostics · 2026Article
- Multidimensional plasticity of natural killer cells in tumours.Cell death & disease · 2025Review
35 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issued
Authors and funding
12 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundNatural killer (NK) cells provide important immune protection from cancer and are a key requirement for particular immunotherapies. There is accumulating evidence that NK cells become dysfunctional during cancer. Overcoming NK cell exhaustion would be an important step to allow them to function optimally in a range of NK cell therapies, including those that depend on autologos circulating NK cells. We have previously demonstrated that NK cells undergo a normal metabolic reprogramming in response to cytokine activation and that this is required for optimal function. The objective of this work was to investigate if cellular metabolism of circulating NK cells is dysregulated in patients with metastatic breast cancer and if so, to gain insights into potential mechanisms underpinning this. Such discoveries would provide important insights into how to unleash the full activity of NK cells for maximum immunotherapy output.
methodsSingle-cell analysis, metabolic flux and confocal analysis of NK cells from patients with metastatic breast cancer and healthy controls
resultsIn addition to reduced interferon-γ production and cytotoxicity, peripheral blood NK cells from patients had clear metabolic deficits including reduced glycolysis and oxidative phosphorylation. There were also distinct morphologically alterations in the mitochondria with increased mitochondrial fragmentation observed. Transforminggrowth factor-β (TGFβ) was identified as a key driver of this phenotype as blocking its activity reversed many metabolic and functional readouts. Expression of glycoprotein-A repetitions predominant (GARP) and latency associated peptide (LAP), which are involved with a novel TGFβ processing pathway, was increased on NK cells from some patients. Blocking the GARP-TGFβ axis recapitulated the effects of TGFβ neutralization, highlighting GARP as a novel NK cell immunotherapy target for the first time.
conclusionsTGFβ contributes to metabolic dysfunction of circulating NK cells in patients with metastatic breast cancer. Blocking TGFβ and/or GARP can restore NK cell metabolism and function and is an important target for improving NK cell-based immunotherapies.
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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.