ArticleMolecular cell2018
Metformin Promotes Antitumor Immunity via Endoplasmic-Reticulum-Associated Degradation of PD-L1.
Article in Molecular cell, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 484 papers, 2 of them syntheses that pooled it.
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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
484 citing papers in PubMed, 2 syntheses or guidelines pooled it, 740 citations in OpenAlex.
- Phytochemicals regulate cancer metabolism through modulation of the AMPK/PGC-1α signaling pathway.BMC cancer · 2024Pooled 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
- Nanoadjuvant-based membrane poration boosts antitumor immunity via modulating mitochondrial metabolism to downregulate PD-L1 and upregulate STING.Bioactive materials · 2027Article
- Metabolites and cancer metastasis.Oncogene · 2026Review
- Post‑translational modification‑governed immune states in cancer immunity: Biomarker implications for checkpoint competence, tumor visibility and immunotherapy resistance (Review).International journal of oncology · 2026Review
- Targeted PD-L1 degradation with an injectable hydrogel reverses chemotherapy-induced compensatory immunosuppression and enhances antitumor immunity.Materials today. Bio · 2026Article
- Immune checkpoints and immunoregulation in metabolic diseases and cancers: pathological mechanisms and therapeutic potential.Signal transduction and targeted therapy · 2026Review
- Complete Response to Tislelizumab in an Elderly Patient With Metastatic Pulmonary Squamous Cell Carcinoma: Potential Synergy With Metformin and Multidisciplinary Management.Clinical case reports · 2026Article
- Dissecting immunosuppressive microenvironment in chemotherapy-resistant colorectal cancer through single-cell transcriptomic analysis.Translational oncology · 2026Article
- CD39British journal of cancer · 2026Article
- Laser-Generated Ultrashort Pulsed Electron Beams Induce p53-Related Alteration of DNA Repair and Cell Death Pathways in Non-Small Cell Lung Cancer Cells.International journal of molecular sciences · 2026Article
- AMPK as a central regulator of necroptosis: mechanistic insights and therapeutic implications.Journal of physiology and biochemistry · 2026Review
- Repurposed ethoxzolamide reprograms antitumor immunity through β-TrCP-dependent PD-L1 ubiquitination.Cell reports. Medicine · 2026Article
- Proton Pump Inhibitor Use and Survival Outcomes in Patients with Advanced Non-Small-Cell Lung Cancer Receiving Immunotherapy: A Real-World Study.Medicina (Kaunas, Lithuania) · 2026Article
- Metformin Induces Ferroptosis and Inhibits Malignant Progression in Diabetic Breast Cancer.Applied biochemistry and biotechnology · 2026Article
- Impact of metformin-based chemo-radiotherapeutic strategies on breast cancer stemness and autophagy-associated gene expression: evidence from ALDH1A1 and LC3 expression analysis.Molecular biology reports · 2026Article
- Deciphering the Anti-Tumor Mechanisms of Metformin Through Reprogramming of the Tumor Microenvironment.Cells · 2026Review
- The mannosyltransferase DPM1 regulates the activity of ER-stress sensor IRE1 in colorectal cancer.Nature communications · 2026Article
- Copper Depletion Nanoparticles Potentiate Cancer Immunotherapy by Avoiding Innate and Adaptive Immune Resistance.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
424 more citing papers are in PubMed but not listed here.
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Authors and funding
28 authors at 7 institutions in 4 countries.
Funding
Abstract
Metformin has been reported to possess antitumor activity and maintain high cytotoxic T lymphocyte (CTL) immune surveillance. However, the functions and detailed mechanisms of metformin's role in cancer immunity are not fully understood. Here, we show that metformin increases CTL activity by reducing the stability and membrane localization of programmed death ligand-1 (PD-L1). Furthermore, we discover that AMP-activated protein kinase (AMPK) activated by metformin directly phosphorylates S195 of PD-L1. S195 phosphorylation induces abnormal PD-L1 glycosylation, resulting in its ER accumulation and ER-associated protein degradation (ERAD). Consistently, tumor tissues from metformin-treated breast cancer patients exhibit reduced PD-L1 levels with AMPK activation. Blocking the inhibitory signal of PD-L1 by metformin enhances CTL activity against cancer cells. Our findings identify a new regulatory mechanism of PD-L1 expression through the ERAD pathway and suggest that the metformin-CTLA4 blockade combination has the potential to increase the efficacy of immunotherapy.
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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.