The DOI matches its Crossref record; 50 of the 50 references it cites were found in a registry or an index.
Metformin Promotes Antitumor Immunity via Endoplasmic-Reticulum-Associated Degradation of PD-L1
Open accessAbstract
Summary 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 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 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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
PD-1 and PD-L1 Immune Checkpoint Blockade to Treat Breast Cancer
Hartkopf, A. D., Taran, F.-A., Wallwiener, M., Walter, C. B., Krämer, B., Grischke, E.-M., & Brucker, S. Y. (2016) · Breast Care · doi:10.1159/000453569 · Cited by 30,845
Adverse Renal Effects of Immune Checkpoint Inhibitors: A Narrative Review
Wanchoo, R., Karam, S., Uppal, N. N., Barta, V. S., Deray, G., Devoe, C., Launay-Vacher, V., Jhaveri, K. D., & on behalf of Cancer and Kidney International Network Workgroup on Immune Checkpoint Inhibitors (2017) · American Journal of Nephrology · doi:10.1159/000455014 · Cited by 15,256
The blockade of immune checkpoints in cancer immunotherapy
Pardoll, D. M. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3239 · Cited by 13,838
Role of AMP-Activated Protein Kinase in Mechanism of Metformin Action
Zhou, G., Myers, R., Li, Y., Chen, Y., Shen, X., Fenyk-Melody, J., Wu, M., Ventre, J., Doebber, T., Fujii, N., et al. (2001) · Journal of Clinical Investigation · doi:10.1172/jci13505 · Cited by 5,652
Nivolumab plus Ipilimumab in Advanced Melanoma
Wolchok, J. D., Kluger, H., Callahan, M. K., Postow, M. A., Rizvi, N. A., Lesokhin, A. M., Segal, N. H., Ariyan, C. E., Gordon, R.-A., Reed, K., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1302369 · Cited by 4,230 · cited 12×
“Together, these data suggested that S195-P by metformin prevents the translocation of PD-L1 to the cell membrane and subsequent PD-1 binding, and therefore, increasing the activity of CTL. Phosphorylation of S195 induces ER-associated degradation of PD-L1 The above findings indicated that PD-L1 S195-p induces a mannos…”
BackgroundInfluentialWatterson, K. R., Bestow, D., Gallagher, J., Hamilton, D. L., Ashford, F. B., Meakin, P. J., & Ashford, M. L. J. (2013) · Neurosignals · doi:10.1159/000334144 · Cited by 3,389
Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy
Topalian, S. L., Taube, J. M., Anders, R. A., & Pardoll, D. M. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.36 · Cited by 2,733
Metformin and reduced risk of cancer in diabetic patients
Evans, J. M. M., Donnelly, L. A., Emslie-Smith, A. M., Alessi, D. R., & Morris, A. D. (2005) · BMJ · doi:10.1136/bmj.38415.708634.f7 · Cited by 2,388
Curran, M. A., Montalvo, W., Yagita, H., & Allison, J. P. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0915174107 · Cited by 1,874
Cellular and molecular mechanisms of metformin: an overview
Viollet, B., Guigas, B., Garcia, N. S., Leclerc, J., Foretz, M., & Andreelli, F. (2012) · Clinical Science · doi:10.1042/cs20110386 · Cited by 1,720
Cited by
Role of the tumor microenvironment in PD-L1/PD-1-mediated tumor immune escape
Jiang, X., Wang, J., Deng, X., Xiong, F., Ge, J., Xiang, B., Wu, X., Ma, J., Zhou, M., Li, X., et al. (2019) · Molecular Cancer · doi:10.1186/s12943-018-0928-4 · Cited by 1,457
The updated landscape of tumor microenvironment and drug repurposing
Jin, M.-Z., & Jin, W.-L. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00280-x · Cited by 1,262
Regulation of PD-L1 expression in the tumor microenvironment
Yi, M., Niu, M., Xu, L., Luo, S., & Wu, K. (2021) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-01027-5 · Cited by 681
HIP1R targets PD-L1 to lysosomal degradation to alter T cell–mediated cytotoxicity
Wang, H., Yao, H., Li, C., Shi, H., Lan, J., Li, Z., Zhang, Y., Liang, L., Fang, J.-Y., & Xu, J. (2019) · Nature Chemical Biology · doi:10.1038/s41589-018-0161-x · Cited by 325
Self-citationPD-L1 degradation pathway and immunotherapy for cancer
Gou, Q., Dong, C., Xu, H., Khan, B., Jin, J., Liu, Q., Shi, J., & Hou, Y. (2020) · Cell Death & Disease · doi:10.1038/s41419-020-03140-2 · Cited by 322
Metadata
- Authors
- Cha, J.-H., Yang, W.-H., Xia, W., Wei, Y., Chan, L.-C., Lim, S.-O., Li, C.-W., Kim, T., Chang, S.-S., Lee, H.-H., Hsu, J. L., Wang, H.-L., Kuo, C.-W., Chang, W.-C., Hadad, S., Purdie, C. A., McCoy, A. M., Cai, S., Tu, Y., Litton, J. K., Mittendorf, E. A., Moulder, S. L., Symmans, W. F., Thompson, A. M., Piwnica-Worms, H., Chen, C.-H., Khoo, K.-H., & Hung, M.-C.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2018-08
- Volume
- 71
- Issue
- 4
- Pages
- 606-620.e7
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W2885288866
- Cited by
- 773
- References
- 50
- FWCI
- 21.06
- Type
- journal article
- Language
- en
- Open access
- bronze
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
How to cite
Cite CoChat for the checks on this page, and the paper for its own findings.
- This page
- CoChat. (2026). Citation check: Metformin Promotes Antitumor Immunity via Endoplasmic-Reticulum-Associated Degradation of PD-L1. https://app.cochat.ai/papers/10.1016/j.molcel.2018.07.030
- The paper
- Cha, J.-H., Yang, W.-H., Xia, W., Wei, Y., Chan, L.-C., Lim, S.-O., Li, C.-W., Kim, T., Chang, S.-S., Lee, H.-H., Hsu, J. L., Wang, H.-L., Kuo, C.-W., Chang, W.-C., Hadad, S., Purdie, C. A., McCoy, A. M., Cai, S., Tu, Y., . . . Hung, M.-C. (2018). Metformin Promotes Antitumor Immunity via Endoplasmic-Reticulum-Associated Degradation of PD-L1. Molecular Cell. https://doi.org/10.1016/j.molcel.2018.07.030
Data sources
Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
