ArticleJournal for immunotherapy of cancer2022
Metformin increases natural killer cell functions in head and neck squamous cell carcinoma through CXCL1 inhibition.
Article in Journal for immunotherapy of cancer, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to 2 registered trials, which are not on this map. Cited by 54 papers, 3 of them syntheses that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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.
Pilot Study of Metformin in Head and Neck Squamous Cell Cancer and Its Effects on Stromal-epithelial Metabolic Uncoupling.
A Phase I Dose-finding Study of Metformin in Combination With Concurrent Cisplatin and Radiation in Patients With Locally Advanced Head and Neck Squamous Cell Carcinoma
Who cites it
54 citing papers in PubMed, 3 syntheses or guidelines pooled it, 65 citations in OpenAlex.
- Effects of metformin on head and neck cancer: an umbrella review.BMC cancer · 2026Pooled it
- Diabetes is associated with elevated mortality, stroke, and osteoradionecrosis in squamous cell carcinomas of the head and neck: a systematic review and meta-analysis.BMC oral health · 2026Pooled it
- Bibliometric analysis of metformin as an immunomodulator (2013-2024).Frontiers in immunology · 2024Pooled it
- A Phase II Feasibility Study Combining Pembrolizumab and Metformin in Patients with Metastatic Head and Neck Cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Trial
- Comparison of Metformin Combinations with Other Repurposed Drugs in the Treatment of Hamster Fibrosarcoma: A Review.Pharmaceuticals (Basel, Switzerland) · 2026Review
- The evolving landscape of the Warburg effect in gastric cancer: From molecular mechanisms to targeted therapy.Clinical and translational medicine · 2026Review
- Metformin as an Innate Immune Modulator: Metabolic and Epigenetic Reprogramming of Innate Immune Cells and Therapeutic Implications.Current issues in molecular biology · 2026Review
- Targeting the NKG2D axis in head and neck squamous cell carcinoma: from molecular insights to clinical applications.Cancer cell international · 2026Review
- Metformin beyond Glycemic Control: New Mechanistic Insights and Expanding Therapeutic Horizons.Diabetes & metabolism journal · 2026Review
- Tumor microenvironment-driven natural killer cell diversity: mechanisms and therapeutic opportunities.Cancer biology & medicine · 2026Review
- Metformin enhances TRAIL-mediated antitumor activity of liver natural killer cells in mice.Scientific reports · 2026Article
- Novel genetic insights into causal effects of potential metformin targets and immune mediation on sepsis.Biology direct · 2026Article
- CXCR2 affects sensitization of radioresistant HPV-negative head and neck squamous cell carcinoma cells by ABT-263.Radiation oncology (London, England) · 2026Article
- PANoptosis-based HNSCPAN-index predicts prognosis and reveals DSCAM as a therapeutic target in head and neck squamous cell carcinoma.PloS one · 2026Article
- CAF-derived BHB modulates FXR1-Kbhb and NK-cell lipid metabolism in osteosarcoma.International journal of biological sciences · 2026Article
- Metformin reshapes the tumor microenvironment and enhances prognosis in invasive pancreatic ductal adenocarcinoma with diabetes mellitus.Journal of gastrointestinal oncology · 2025Article
- Understanding the Tumor Microenvironment and Therapy Resistance in Head and Neck Squamous Cell Carcinoma.Cells · 2025Review
- Effect of metformin on hypoxia-associated gene expression in oral cavity squamous cell carcinoma in non-diabetic patients - a prospective window of opportunity study.European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery · 2025Article
- Antitumor Effects of Metformin in Squamous Cell Carcinoma under Leptin Treatment Conditions.Preventive nutrition and food science · 2025Article
- Mapping the current research landscape of metformin in cancer based on bibliometric analysis.Discover oncology · 2025Article
Corrections and comments
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Authors and funding
15 authors at 6 institutions in 1 country.
Funding
Abstract
backgroundMetformin slows tumor growth and progression in vitro, and in combination with chemoradiotherapy, resulted in high overall survival in patients with head and neck cancer squamous cell carcinoma (HNSCC) in our phase 1 clinical trial (NCT02325401). Metformin is also postulated to activate an antitumor immune response. Here, we investigate immunologic effects of metformin on natural killer (NK) and natural killer T cells, including results from two phase I open-label studies in patients with HNSCC treated with metformin (NCT02325401, NCT02083692).
methodsPeripheral blood was collected before and after metformin treatment or from newly diagnosed patients with HNSCC. Peripheral immune cell phenotypes were evaluated using flow cytometry, cytokine expression by ELISA and/or IsoLight, and NK cell-mediated cytotoxicity was determined with a flow-based NK cell cytotoxicity assay (NKCA). Patient tumor immune infiltration before and after metformin treatment was analyzed with immunofluorescence. NK cells were treated with either vehicle or metformin and analyzed by RNA sequencing (RNA-seq). NK cells were then treated with inhibitors of significant pathways determined by RNA-seq and analyzed by NKCA, ELISA, and western blot analyses.
resultsIncreased peripheral NK cell activated populations were observed in patients treated with metformin. NK cell tumor infiltration was enhanced in patients with HNSCC treated with metformin preoperatively. Metformin increased antitumorigenic cytokines ex vivo, including significant increases in perforin. Metformin increased HNSCC NK cell cytotoxicity and inhibited the CXCL1 pathway while stimulating the STAT1 pathway within HNSCC NK cells. Exogenous CXCL1 prevented metformin-enhanced NK cell-mediated cytotoxicity. Metformin-mediated NK cell cytotoxicity was found to be AMP-activated protein kinase independent, but dependent on both mechanistic target of rapamycin and pSTAT1.
conclusionsOur data identifies a new role for metformin-mediated immune antitumorigenic function through NK cell-mediated cytotoxicity and downregulation of CXCL1 in HNSCC. These findings will inform future immunomodulating therapies in HNSCC.
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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.