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Previous studies have demonstrated that metformin suppresses tumor progression by regulating multiple signaling pathways, including the AMPK, PI3K\/AKT\/mTOR, and JNK pathways. However, most previous studies have focused on its direct effects on tumor cells, with limited attention to its effects in the TME. The TME constitutes a multifaceted ecosystem that drives tumor development and therapeutic resistance via physical barrier formation, immune evasion, and abnormal angiogenesis. In this review, we systematically summarize the impact and underlying regulatory mechanisms of metformin on distinct components of the TME. In addition, we discuss the individual and combined roles of metformin in immunity and inflammation, as well as vascular, matrix, and metabolic regulation. By elucidating the mechanisms of metformin-mediated TME reprogramming, we aim to provide new perspectives for understanding its anti-tumor effects and facilitating its clinical translation in cancer therapy.<\/jats:p>","DOI":"10.3390\/cells15131183","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T15:27:37Z","timestamp":1782746857000},"page":"1183","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Deciphering the Anti-Tumor Mechanisms of Metformin Through Reprogramming of the Tumor Microenvironment"],"prefix":"10.3390","volume":"15","author":[{"given":"Ting","family":"Zeng","sequence":"first","affiliation":[{"name":"NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410078, China"},{"name":"Cancer Research Institute, Xiangya School of Basic Medical Sciences, Central South University, Changsha 410078, China"},{"name":"The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha 410078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lemei","family":"Zheng","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410078, China"},{"name":"Cancer Research Institute, Xiangya School of Basic Medical Sciences, Central South University, Changsha 410078, China"},{"name":"The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha 410078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianxia","family":"Wei","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and the 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4938-5397","authenticated-orcid":false,"given":"Ming","family":"Zhou","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410078, China"},{"name":"Cancer Research Institute, Xiangya School of Basic Medical Sciences, Central South University, Changsha 410078, China"},{"name":"The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha 410078, China"},{"name":"Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengna","family":"Li","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410078, China"},{"name":"Cancer Research Institute, Xiangya School of Basic Medical Sciences, Central South University, Changsha 410078, China"},{"name":"Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2184","DOI":"10.1093\/annonc\/mdw410","article-title":"Metformin as an adjuvant treatment for cancer: A systematic review and meta-analysis","volume":"27","author":"Coyle","year":"2016","journal-title":"Ann. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1158\/2326-6066.CIR-16-0103","article-title":"Efficacy of PD-1 Blockade Is Potentiated by Metformin-Induced Reduction of Tumor Hypoxia","volume":"5","author":"Scharping","year":"2017","journal-title":"Cancer Immunol. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"391","DOI":"10.2147\/BCTT.S384702","article-title":"Metformin Inducing the Change of Functional and Exhausted Phenotypic Tumor-Infiltrated Lymphocytes and the Correlation with JNK Signal Pathway in Triple-Negative Breast Cancer","volume":"14","author":"Wang","year":"2022","journal-title":"Breast Cancer Targets Ther."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1879","DOI":"10.1182\/blood.2023020142","article-title":"EGR1-mediated metabolic reprogramming to oxidative phosphorylation contributes to ibrutinib resistance in B-cell lymphoma","volume":"142","author":"Liu","year":"2023","journal-title":"Blood"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Coronel-Hern\u00e1ndez, J., Salgado-Garc\u00eda, R., Le\u00f3n, D.C.-D., Jacobo-Herrera, N., Millan-Catalan, O., Delgado-Waldo, I., Campos-Parra, A.D., Rodr\u00edguez-Morales, M., Delgado-Buenrostro, N.L., and P\u00e9rez-Plasencia, C. (2021). Combination of Metformin, Sodium Oxamate and Doxorubicin Induces Apoptosis and Autophagy in Colorectal Cancer Cells via Downregulation HIF-1\u03b1. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.594200"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5227","DOI":"10.1007\/s12013-025-01840-0","article-title":"Effects of Metformin Treatment Against Endometrial Cancer Cells Cultured In Vitro or Grafted into Female Balb\/C Nude Mice: Insights into Cell Response and IGF-1R and PI3K\/AKT\/mTOR Signaling Pathways","volume":"83","author":"Ramos","year":"2025","journal-title":"Cell Biochem. Biophys."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1158\/2159-8290.CD-20-1808","article-title":"Therapeutic Targeting of the Tumor Microenvironment","volume":"11","author":"Bejarano","year":"2021","journal-title":"Cancer Discov."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Bi, J., and Tian, Z. (2019). NK Cell Dysfunction and Checkpoint Immunotherapy. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.01999"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2223","DOI":"10.1038\/s41388-018-0582-8","article-title":"The ERK and JNK pathways in the regulation of metabolic reprogramming","volume":"38","author":"Papa","year":"2018","journal-title":"Oncogene"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1038\/s41586-022-04431-8","article-title":"Low-dose metformin targets the lysosomal AMPK pathway through PEN2","volume":"603","author":"Ma","year":"2022","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1186\/s13046-019-1211-2","article-title":"Metformin inhibits metastatic breast cancer progression and improves chemosensitivity by inducing vessel normalization via PDGF-B downregulation","volume":"38","author":"Wang","year":"2019","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2358","DOI":"10.1158\/0008-5472.CAN-22-3042","article-title":"Metformin Reprograms Tryptophan Metabolism to Stimulate CD8+ T-cell Function in Colorectal Cancer","volume":"83","author":"Huang","year":"2023","journal-title":"Cancer Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e005719","DOI":"10.1136\/jitc-2022-005719","article-title":"Metformin improves cancer immunotherapy by directly rescuing tumor-infiltrating CD8 T lymphocytes from hypoxia-induced immunosuppression","volume":"11","author":"Finisguerra","year":"2023","journal-title":"J. Immunother. Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1186\/s13075-019-1904-0","article-title":"Metformin improves salivary gland inflammation and hypofunction in murine Sj\u00f6gren\u2019s syndrome","volume":"21","author":"Kim","year":"2019","journal-title":"Arthritis Res. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"20706","DOI":"10.18632\/oncotarget.14982","article-title":"Metformin-treated cancer cells modulate macrophage polarization through AMPK-NF-\u03baB signaling","volume":"8","author":"Chiang","year":"2017","journal-title":"Oncotarget"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"151709","DOI":"10.1016\/j.acthis.2021.151709","article-title":"Anti-cancer effect of metformin on the metastasis and invasion of primary breast cancer cells through mediating NF-kB activity","volume":"123","author":"Yenmis","year":"2021","journal-title":"Acta Histochem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"216497","DOI":"10.1016\/j.canlet.2023.216497","article-title":"Targeting TAM-secreted S100A9 effectively enhances the tumor-suppressive effect of metformin in treating lung adenocarcinoma","volume":"581","author":"Sui","year":"2023","journal-title":"Cancer Lett."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"eabq1475","DOI":"10.1126\/sciadv.abq1475","article-title":"Metformin prevents age-associated ovarian fibrosis by modulating the immune landscape in female mice","volume":"8","author":"Landry","year":"2022","journal-title":"Sci. Adv."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1038\/s41598-022-05470-x","article-title":"Metformin sensitizes leukemic cells to cytotoxic lymphocytes by increasing expression of intercellular adhesion molecule-1 (ICAM-1)","volume":"12","author":"Brualla","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e002772","DOI":"10.1136\/jitc-2021-002772","article-title":"Sensitizing tumors to anti-PD-1 therapy by promoting NK and CD8+ T cells via pharmacological activation of FOXO3","volume":"9","author":"Chung","year":"2021","journal-title":"J. Immunother. Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e2105376","DOI":"10.1002\/advs.202105376","article-title":"Biomimetic Nanocarriers Guide Extracellular ATP Homeostasis to Remodel Energy Metabolism for Activating Innate and Adaptive Immunity System","volume":"9","author":"Wu","year":"2022","journal-title":"Adv. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"102052","DOI":"10.1016\/j.tranon.2024.102052","article-title":"Metformin induces tumor immunogenic cell death in ovarian cancer by activating AMPK pathway","volume":"47","author":"Chen","year":"2024","journal-title":"Transl. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Roussot, N., Ghiringhelli, F., and R\u00e9b\u00e9, C. (2022). Tumor Immunogenic Cell Death as a Mediator of Intratumor CD8 T-Cell Recruitment. Cells, 11.","DOI":"10.3390\/cells11223672"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1007\/s00018-023-04932-3","article-title":"Metformin induces tolerogenicity of dendritic cells by promoting metabolic reprogramming","volume":"80","author":"Liu","year":"2023","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s12943-024-02208-3","article-title":"Myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment and their targeting in cancer therapy","volume":"24","author":"He","year":"2025","journal-title":"Mol. Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1038\/s41416-018-0333-1","article-title":"Immunosuppression mediated by myeloid-derived suppressor cells (MDSCs) during tumour progression","volume":"120","author":"Groth","year":"2018","journal-title":"Br. J. Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e1320011","DOI":"10.1080\/2162402X.2017.1320011","article-title":"CD39\/CD73 upregulation on myeloid-derived suppressor cells via TGF-\u03b2-mTOR-HIF-1 signaling in patients with non-small cell lung cancer","volume":"6","author":"Li","year":"2017","journal-title":"OncoImmunology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1779","DOI":"10.1158\/0008-5472.CAN-17-2460","article-title":"Metformin-Induced Reduction of CD39 and CD73 Blocks Myeloid-Derived Suppressor Cell Activity in Patients with Ovarian Cancer","volume":"78","author":"Li","year":"2018","journal-title":"Cancer Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.canlet.2016.12.031","article-title":"Metformin inhibits castration-induced EMT in prostate cancer by repressing COX2\/PGE2\/STAT3 axis","volume":"389","author":"Tong","year":"2017","journal-title":"Cancer Lett."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"eadq4409","DOI":"10.1126\/scitranslmed.adq4409","article-title":"A gut Eggerthella lenta\u2013derived metabolite impairs neutrophil function to aggravate bacterial lung infection","volume":"17","author":"Wang","year":"2025","journal-title":"Sci. Transl. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"14848","DOI":"10.1021\/acsnano.4c18627","article-title":"A Metformin-Based Multifunctional Nanoplatform as a DNA Damage Amplifier for Maximized Radio-Immunotherapy to Overcome Radiotherapy Resistance","volume":"19","author":"He","year":"2025","journal-title":"ACS Nano"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1016\/j.molcel.2018.07.030","article-title":"Metformin Promotes Antitumor Immunity via Endoplasmic-Reticulum-Associated Degradation of PD-L1","volume":"71","author":"Cha","year":"2018","journal-title":"Mol. Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e002773","DOI":"10.1136\/jitc-2021-002773","article-title":"Metformin generates profound alterations in systemic and tumor immunity with associated antitumor effects","volume":"9","author":"Veeramachaneni","year":"2021","journal-title":"J. Immunother. Cancer"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Yang, S.-Y., Long, J., Huang, M.-X., Luo, P.-Y., Bian, Z.-H., Xu, Y.-F., Wang, C.-B., Yang, S.-H., Li, L., and Selmi, C. (2021). Characterization of Organ-Specific Regulatory B Cells Using Single-Cell RNA Sequencing. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.711980"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2661","DOI":"10.4049\/jimmunol.1403088","article-title":"Metformin Suppresses Systemic Autoimmunity in Roquinsan\/san Mice through Inhibiting B Cell Differentiation into Plasma Cells via Regulation of AMPK\/mTOR\/STAT3","volume":"198","author":"Lee","year":"2017","journal-title":"J. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1038\/s41586-023-06017-4","article-title":"A druggable copper-signalling pathway that drives inflammation","volume":"617","author":"Solier","year":"2023","journal-title":"Nature"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"112948","DOI":"10.1016\/j.yexcr.2021.112948","article-title":"Evidence of immunogenic cancer cell death induced by honey-processed Astragalus polysaccharides in vitro and in vivo","volume":"410","author":"Sha","year":"2022","journal-title":"Exp. Cell Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1038\/nature01322","article-title":"Inflammation and cancer","volume":"420","author":"Coussens","year":"2002","journal-title":"Nature"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1016\/j.immuni.2021.05.004","article-title":"Metformin inhibition of mitochondrial ATP and DNA synthesis abrogates NLRP3 inflammasome activation and pulmonary inflammation","volume":"54","author":"Xian","year":"2021","journal-title":"Immunity"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1097\/HJH.0000000000003892","article-title":"The effects of metformin on inflammation and apoptosis in rats with preeclampsia","volume":"43","author":"Chen","year":"2024","journal-title":"J. Hypertens."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"73892","DOI":"10.18632\/oncotarget.18029","article-title":"Suppression of hypoxia-induced excessive angiogenesis by metformin via elevating tumor blood perfusion","volume":"8","author":"Wang","year":"2017","journal-title":"Oncotarget"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e2404778121","DOI":"10.1073\/pnas.2404778121","article-title":"Metformin synergizes with PD-1 blockade to promote normalization of tumor vessels via CD8T cells and IFN\u03b3","volume":"121","author":"Tokumasu","year":"2024","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.cell.2010.03.015","article-title":"Matrix metalloproteinases: Regulators of the tumor microenvironment","volume":"141","author":"Kessenbrock","year":"2010","journal-title":"Cell"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1038\/s41467-020-20723-x","article-title":"Boosting anti-PD-1 therapy with metformin-loaded macrophage-derived microparticles","volume":"12","author":"Wei","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"63461","DOI":"10.18632\/oncotarget.18831","article-title":"Pancreatic cancer-derived exosomes promote tumor metastasis and liver pre-metastatic niche formation","volume":"8","author":"Yu","year":"2017","journal-title":"Oncotarget"},{"key":"ref_46","first-page":"1785","article-title":"MiR-182 promotes proliferation and invasion and elevates the HIF-1\u03b1-VEGF-A axis in breast cancer cells by targeting FBXW7","volume":"6","author":"Chiang","year":"2016","journal-title":"Am. J. Cancer Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.3892\/ol.2017.6324","article-title":"miRNA-21 enhances chemoresistance to cisplatin in epithelial ovarian cancer by negatively regulating PTEN","volume":"14","author":"Yu","year":"2017","journal-title":"Oncol. Lett."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.arcmed.2020.10.007","article-title":"Metformin Increases Exosome Biogenesis and Secretion in U87 MG Human Glioblastoma Cells: A Possible Mechanism of Therapeutic Resistance","volume":"52","author":"Soraya","year":"2021","journal-title":"Arch. Med. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1945","DOI":"10.1016\/j.ccell.2023.09.012","article-title":"Tumor-resident Lactobacillus iners confer chemoradiation resistance through lactate-induced metabolic rewiring","volume":"41","author":"Colbert","year":"2023","journal-title":"Cancer Cell"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.taap.2019.01.004","article-title":"Metformin delays AKT\/c-Met-driven hepatocarcinogenesis by regulating signaling pathways for de novo lipogenesis and ATP generation","volume":"365","author":"Zhang","year":"2019","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3047","DOI":"10.1016\/j.celrep.2018.11.043","article-title":"Dual Inhibition of the Lactate Transporters MCT1 and MCT4 Is Synthetic Lethal with Metformin due to NAD+ Depletion in Cancer Cells","volume":"25","author":"Benjamin","year":"2018","journal-title":"Cell Rep."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1907","DOI":"10.2147\/DDDT.S409373","article-title":"Metformin: A Review of Potential Mechanism and Therapeutic Utility Beyond Diabetes","volume":"17","author":"Dutta","year":"2023","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.1158\/2326-6066.CIR-15-0036","article-title":"Inhibition of Fatty Acid Oxidation Modulates Immunosuppressive Functions of Myeloid-Derived Suppressor Cells and Enhances Cancer Therapies","volume":"3","author":"Hossain","year":"2015","journal-title":"Cancer Immunol. Res."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Watzling, M., Klaus, L., Weidemeier, T., Horder, H., Ebert, R., Blunk, T., and Bauer-Kreisel, P. (2023). Three-Dimensional Breast Cancer Model to Investigate CCL5\/CCR1 Expression Mediated by Direct Contact between Breast Cancer Cells and Adipose-Derived Stromal Cells or Adipocytes. Cancers, 15.","DOI":"10.3390\/cancers15133501"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1828","DOI":"10.1097\/HEP.0000000000000314","article-title":"Hepatic mitochondrial NAD+ transporter SLC25A47 activates AMPK\u03b1 mediating lipid metabolism and tumorigenesis","volume":"78","author":"Cheng","year":"2023","journal-title":"Hepatology"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s40170-020-0209-8","article-title":"Glutaminase-1 (GLS1) inhibition limits metastatic progression in osteosarcoma","volume":"8","author":"Ren","year":"2020","journal-title":"Cancer Metab."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"6391","DOI":"10.1021\/acs.molpharmaceut.3c00772","article-title":"Metformin-Loaded Hyaluronic Acid-Derived Carbon Dots for Targeted Therapy against Hepatocellular Carcinoma by Glutamine Metabolic Reprogramming","volume":"20","author":"Ghosh","year":"2023","journal-title":"Mol. Pharm."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"E5328","DOI":"10.1073\/pnas.1611406113","article-title":"Combination therapy with BPTES nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer","volume":"113","author":"Elgogary","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"110797","DOI":"10.1016\/j.exger.2019.110797","article-title":"Kynurenine signaling through the aryl hydrocarbon receptor: Implications for aging and healthspan","volume":"130","author":"Kaiser","year":"2020","journal-title":"Exp. Gerontol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1016\/j.cell.2021.01.018","article-title":"Structural basis for IL-12 and IL-23 receptor sharing reveals a gateway for shaping actions on T versus NK cells","volume":"184","author":"Glassman","year":"2021","journal-title":"Cell"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/nri1001","article-title":"Interleukin-12 and the regulation of innate resistance and adaptive immunity","volume":"3","author":"Trinchieri","year":"2003","journal-title":"Nat. Rev. Immunol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"101661","DOI":"10.1016\/j.molmet.2022.101661","article-title":"AMPK integrates metabolite and kinase-based immunometabolic control in macrophages","volume":"68","author":"Phair","year":"2022","journal-title":"Mol. Metab."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1016\/j.ccell.2023.02.009","article-title":"Functional states of myeloid cells in cancer","volume":"41","author":"Tyurina","year":"2023","journal-title":"Cancer Cell"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"e1442167","DOI":"10.1080\/2162402X.2018.1442167","article-title":"Metformin blocks myeloid-derived suppressor cell accumulation through AMPK-DACH1-CXCL1 axis","volume":"7","author":"Qin","year":"2018","journal-title":"OncoImmunology"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1038\/nrclinonc.2016.217","article-title":"Tumour-associated macrophages as treatment targets in oncology","volume":"14","author":"Mantovani","year":"2017","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1007\/s00210-024-03358-3","article-title":"Metformin and the PI3K\/AKT signaling pathway: Implications for cancer, cardiovascular, and central nervous system diseases","volume":"398","author":"Ahmadabad","year":"2024","journal-title":"Naunyn-Schmiedeberg\u2019s Arch. Pharmacol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1038\/nrc.2016.73","article-title":"The biology and function of fibroblasts in cancer","volume":"16","author":"Kalluri","year":"2016","journal-title":"Nat. Rev. Cancer"},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"You, W.-K., and Stallcup, W.B. (2017). Localization of VEGF to Vascular ECM Is an Important Aspect of Tumor Angiogenesis. Cancers, 9.","DOI":"10.3390\/cancers9080097"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1083\/jcb.152.3.633","article-title":"Matrix Attachment Regulates FAS-Induced Apoptosis in Endothelial Cells","volume":"152","author":"Aoudjit","year":"2001","journal-title":"J. Cell Biol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1186\/s12951-023-02020-z","article-title":"HIF-1\u03b1 increases the osteogenic capacity of ADSCs by coupling angiogenesis and osteogenesis via the HIF-1\u03b1\/VEGF\/AKT\/mTOR signaling pathway","volume":"21","author":"Song","year":"2023","journal-title":"J. Nanobiotechnol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"155690","DOI":"10.1016\/j.phymed.2024.155690","article-title":"Polyphyllin I ameliorates gefitinib resistance and inhibits the VEGF\/VEGFR2\/p38 pathway by targeting HIF-1a in lung adenocarcinoma","volume":"129","author":"Zhang","year":"2024","journal-title":"Phytomedicine"},{"key":"ref_72","first-page":"506","article-title":"Metformin exerts synergistic anti-proliferative effects with liraglutide in human umbilical vein endothelial cells (HUVECs)","volume":"25","author":"Shadboorestan","year":"2022","journal-title":"Iran. J. Basic Med. Sci."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"819","DOI":"10.3748\/wjg.v24.i7.819","article-title":"Metformin attenuates motility, contraction, and fibrogenic response of hepatic stellate cells in vivo and in vitro by activating AMP-activated protein kinase","volume":"24","author":"Li","year":"2018","journal-title":"World J. Gastroenterol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"119421","DOI":"10.1016\/j.biomaterials.2019.119421","article-title":"Modulation of redox metabolism negates cancer-associated fibroblasts-induced treatment resistance in a heterotypic 3D culture platform of pancreatic cancer","volume":"222","author":"Broekgaarden","year":"2019","journal-title":"Biomaterials"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1016\/j.molcel.2016.02.011","article-title":"Mitochondria and Cancer","volume":"61","author":"Zong","year":"2016","journal-title":"Mol. Cell"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1038\/s41392-022-01151-3","article-title":"Lactate metabolism in human health and disease","volume":"7","author":"Li","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/j.cmet.2016.08.011","article-title":"LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells","volume":"24","author":"Brand","year":"2016","journal-title":"Cell Metab."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.ccell.2022.01.001","article-title":"Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments","volume":"40","author":"Kumagai","year":"2022","journal-title":"Cancer Cell"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"107451","DOI":"10.1016\/j.pharmthera.2019.107451","article-title":"Lactate\/GPR81 signaling and proton motive force in cancer: Role in angiogenesis, immune escape, nutrition, and Warburg phenomenon","volume":"206","author":"Brown","year":"2020","journal-title":"Pharmacol. Ther."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1124\/pr.119.018762","article-title":"Monocarboxylate Transporters (SLC16): Function, Regulation, and Role in Health and Disease","volume":"72","author":"Felmlee","year":"2020","journal-title":"Pharmacol. Rev."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"189175","DOI":"10.1016\/j.bbcan.2024.189175","article-title":"ROS: A \u201cbooster\u201d for chronic inflammation and tumor metastasis","volume":"1879","author":"Chen","year":"2024","journal-title":"Biochim. Biophys. Acta (BBA) Rev. Cancer"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1016\/j.ccell.2023.02.016","article-title":"The evolving tumor microenvironment: From cancer initiation to metastatic outgrowth","volume":"41","author":"Joyce","year":"2023","journal-title":"Cancer Cell."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1038\/s41419-021-04478-x","article-title":"Metformin prevents methylglyoxal-induced apoptosis by suppressing oxidative stress in vitro and in vivo","volume":"13","author":"Wang","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.1126\/science.abh2841","article-title":"Tumor necrosis factor induces pathogenic mitochondrial ROS in tuberculosis through reverse electron transport","volume":"376","author":"Roca","year":"2022","journal-title":"Science"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1136\/gutjnl-2024-332398","article-title":"Interplay between gut microbiome, host genetic and epigenetic modifications in MASLD and MASLD-related hepatocellular carcinoma","volume":"74","author":"Ha","year":"2024","journal-title":"Gut"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1919","DOI":"10.1038\/s41591-018-0222-4","article-title":"Gut microbiota and intestinal FXR mediate the clinical benefits of metformin","volume":"24","author":"Sun","year":"2018","journal-title":"Nat. Med."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"2112","DOI":"10.1136\/gutjnl-2023-330291","article-title":"Roseburia intestinalis generated butyrate boosts anti-PD-1 efficacy in colorectal cancer by activating cytotoxic CD8+ T cells","volume":"72","author":"Kang","year":"2023","journal-title":"Gut"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1038\/nm1609","article-title":"Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer","volume":"13","author":"Nagaraj","year":"2007","journal-title":"Nat. Med."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"2307542","DOI":"10.1080\/19490976.2024.2307542","article-title":"Gut microbiota modulate CD8 + T cell immunity in gastric cancer through Butyrate\/GPR109A\/HOPX","volume":"16","author":"Yu","year":"2024","journal-title":"Gut Microbes"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"RP89045","DOI":"10.7554\/eLife.89045.4","article-title":"Gut microbiota-derived gamma-aminobutyric acid from metformin treatment reduces hepatic ischemia\/reperfusion injury through inhibiting ferroptosis","volume":"12","author":"Wang","year":"2024","journal-title":"eLife"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"e007235","DOI":"10.1136\/jitc-2023-007235","article-title":"Phase II trial of nivolumab and metformin in patients with treatment-refractory microsatellite stable metastatic colorectal cancer","volume":"11","author":"Akce","year":"2023","journal-title":"J. Immunother. Cancer"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"4921","DOI":"10.1158\/1078-0432.CCR-20-0113","article-title":"Low-Dose Metformin Reprograms the Tumor Immune Microenvironment in Human Esophageal Cancer: Results of a Phase II Clinical Trial","volume":"26","author":"Wang","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1250684","DOI":"10.1126\/science.1250684","article-title":"mTOR- and HIF-1\u03b1\u2013mediated aerobic glycolysis as metabolic basis for trained immunity","volume":"345","author":"Cheng","year":"2014","journal-title":"Science"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1186\/s12943-025-02302-0","article-title":"Inhibition of 6-phosphogluconate dehydrogenase suppresses esophageal squamous cell carcinoma growth and enhances the anti-tumor effects of metformin via the AMPK\/mTOR pathway","volume":"24","author":"Wang","year":"2025","journal-title":"Mol. Cancer"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1007\/s12032-022-01722-y","article-title":"Metformin inhibits the development and metastasis of colorectal cancer","volume":"39","author":"Sugiura","year":"2022","journal-title":"Med. Oncol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"8250","DOI":"10.18632\/oncotarget.14159","article-title":"Stattic and metformin inhibit brain tumor initiating cells by reducing STAT3-phosphorylation","volume":"8","author":"Leidgens","year":"2016","journal-title":"Oncotarget"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"371","DOI":"10.3892\/or.2020.7595","article-title":"Metformin inhibits TGF-\u03b21-induced epithelial-mesenchymal transition and liver metastasis of pancreatic cancer cells","volume":"44","author":"Yoshida","year":"2020","journal-title":"Oncol. Rep."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"145796","DOI":"10.1016\/j.gene.2021.145796","article-title":"Up-down regulation of HIF-1\u03b1 in cancer progression","volume":"798","author":"Rashid","year":"2021","journal-title":"Gene"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"101135","DOI":"10.1016\/j.aohep.2023.101135","article-title":"Metformin ameliorates liver fibrosis induced by congestive hepatopathy via the mTOR\/HIF-1\u03b1 signaling pathway","volume":"28","author":"Yang","year":"2023","journal-title":"Ann. Hepatol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1016\/j.ccell.2025.02.015","article-title":"Hypoxia inducible factor-1\u03b1 drives cancer resistance to cuproptosis","volume":"43","author":"Yang","year":"2025","journal-title":"Cancer Cell"},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Duchatel, R.J., Jackson, E.R., Parackal, S.G., Kiltschewskij, D., Findlay, I.J., Mannan, A., Staudt, D.E., Thomas, B.C., Germon, Z.P., and Laternser, S. (2024). PI3K\/mTOR is a therapeutically targetable genetic dependency in diffuse intrinsic pontine glioma. J. Clin. Investig., 134.","DOI":"10.1172\/JCI170329"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1038\/s41392-025-02451-0","article-title":"Alpha-enolase influences ATP pool of cytoplasm and lactate homeostasis by regulating glycolysis in gastric cancer","volume":"10","author":"Shu","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1093\/procel\/pwad065","article-title":"Follicle stimulating hormone controls granulosa cell glutamine synthesis to regulate ovulation","volume":"15","author":"Zhang","year":"2024","journal-title":"Protein Cell"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"4030","DOI":"10.1158\/1078-0432.CCR-17-3167","article-title":"Metformin Targets Mitochondrial Glycerophosphate Dehydrogenase to Control Rate of Oxidative Phosphorylation and Growth of Thyroid Cancer In Vitro and In Vivo","volume":"24","author":"Thakur","year":"2018","journal-title":"Clin. Cancer Res."},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Yusein-Myashkova, S., Vladimirova, D., Gospodinov, A., Ugrinova, I., and Todorova, J. (2025). Metformin Inhibits Cell Motility and Proliferation of Triple-Negative Breast Cancer Cells by Blocking HMGB1\/RAGE Signaling. Cells, 14.","DOI":"10.3390\/cells14080590"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"993","DOI":"10.7150\/thno.104872","article-title":"Metformin-based nanomedicines for reprogramming tumor immune microenvironment","volume":"15","author":"Liu","year":"2025","journal-title":"Theranostics"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1016\/j.cmet.2013.09.005","article-title":"AMP as a Low-Energy Charge Signal Autonomously Initiates Assembly of AXIN-AMPK-LKB1 Complex for AMPK Activation","volume":"18","author":"Zhang","year":"2013","journal-title":"Cell Metab."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1124\/pharmrev.121.000445","article-title":"International Union of Basic and Clinical Pharmacology. CXII: Adenosine Receptors: A Further Update","volume":"74","author":"Ijzerman","year":"2022","journal-title":"Pharmacol. Rev."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1016\/j.cmet.2010.04.001","article-title":"Use of Cells Expressing \u03b3 Subunit Variants to Identify Diverse Mechanisms of AMPK Activation","volume":"11","author":"Hawley","year":"2010","journal-title":"Cell Metab."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1016\/j.cmet.2014.06.014","article-title":"The Lysosomal v-ATPase-Ragulator Complex Is a Common Activator for AMPK and mTORC1, Acting as a Switch between Catabolism and Anabolism","volume":"20","author":"Zhang","year":"2014","journal-title":"Cell Metab."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1002\/hep.32404","article-title":"FGF4 protects the liver from nonalcoholic fatty liver disease by activating the AMP-activated protein kinase\u2013Caspase 6 signal axis","volume":"76","author":"Song","year":"2022","journal-title":"Hepatology"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1186\/s12974-019-1411-x","article-title":"AMPK activation attenuates inflammatory pain through inhibiting NF-\u03baB activation and IL-1\u03b2 expression","volume":"16","author":"Xiang","year":"2019","journal-title":"J. Neuroinflamm."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1146\/annurev.immunol.021908.132641","article-title":"Regulation and Function of NF-\u03baB Transcription Factors in the Immune System","volume":"27","author":"Vallabhapurapu","year":"2009","journal-title":"Annu. Rev. Immunol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1038\/nrclinonc.2018.8","article-title":"Targeting the IL-6\/JAK\/STAT3 signalling axis in cancer","volume":"15","author":"Johnson","year":"2018","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.ccell.2024.11.011","article-title":"Cytokines in cancer","volume":"43","author":"Kureshi","year":"2024","journal-title":"Cancer Cell"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1136\/ard-2023-223850","article-title":"Selectivity, efficacy and safety of JAKinibs: New evidence for a still evolving story","volume":"83","author":"Bonelli","year":"2024","journal-title":"Ann. Rheum. Dis."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"109770","DOI":"10.1016\/j.intimp.2023.109770","article-title":"STAT3 as a therapeutic target in the metformin-related treatment","volume":"116","author":"Zhang","year":"2023","journal-title":"Int. Immunopharmacol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1186\/s12943-020-01258-7","article-title":"Targeting STAT3 in Cancer Immunotherapy","volume":"19","author":"Zou","year":"2020","journal-title":"Mol. Cancer"},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"Saito, A., Horie, M., and Nagase, T. (2018). TGF-\u03b2 Signaling in Lung Health and Disease. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19082460"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1038\/nrm3906","article-title":"Preconditioning the ECM for fibrosis","volume":"15","author":"Minton","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1186\/s12943-022-01569-x","article-title":"Targeting TGF-\u03b2 signal transduction for fibrosis and cancer therapy","volume":"21","author":"Peng","year":"2022","journal-title":"Mol. Cancer"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1038\/nature02006","article-title":"Smad-dependent and Smad-independent pathways in TGF-\u03b2 family signalling","volume":"425","author":"Derynck","year":"2003","journal-title":"Nature"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1186\/1756-8722-6-50","article-title":"Signal transduction inhibitors in treatment of myelodysplastic syndromes","volume":"6","author":"Bachegowda","year":"2013","journal-title":"J. Hematol. Oncol."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1038\/nrc1187","article-title":"Targeting HIF-1 for cancer therapy","volume":"3","author":"Semenza","year":"2003","journal-title":"Nat. Rev. Cancer"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"111484","DOI":"10.1016\/j.mce.2021.111484","article-title":"Antiproliferative effects of metformin in cellular models of pheochromocytoma","volume":"539","author":"Meireles","year":"2022","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1017\/S1462399411002109","article-title":"PI3K\/AKT, MAPK and AMPK signalling: Protein kinases in glucose homeostasis","volume":"14","author":"Schultze","year":"2012","journal-title":"Expert. Rev. Mol. Med."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1097\/XCS.0000000000000205","article-title":"Effect of Metformin on HIF-1\u03b1 Signaling and Postoperative Adhesion Formation","volume":"234","author":"Biller","year":"2022","journal-title":"J. Am. Coll. Surg."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.jhep.2023.10.006","article-title":"Endothelial DGKG promotes tumor angiogenesis and immune evasion in hepatocellular carcinoma","volume":"80","author":"Zhang","year":"2023","journal-title":"J. Hepatol."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"12044","DOI":"10.7150\/thno.47901","article-title":"ITGB2-mediated metabolic switch in CAFs promotes OSCC proliferation by oxidation of NADH in mitochondrial oxidative phosphorylation system","volume":"10","author":"Zhang","year":"2020","journal-title":"Theranostics"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"3113","DOI":"10.7150\/ijbs.89942","article-title":"The PI3K\/Akt Pathway and Glucose Metabolism: A Dangerous Liaison in Cancer","volume":"20","author":"Fontana","year":"2024","journal-title":"Int. J. Biol. Sci."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1177\/1947601913486349","article-title":"The 2 Faces of JNK Signaling in Cancer","volume":"4","author":"Tournier","year":"2013","journal-title":"Genes Cancer"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"682","DOI":"10.18632\/genesandcancer.155","article-title":"JNK-signaling: A multiplexing hub in programmed cell death","volume":"8","author":"Dhanasekaran","year":"2017","journal-title":"Genes Cancer"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1038\/nrc2694","article-title":"Signal integration by JNK and p38 MAPK pathways in cancer development","volume":"9","author":"Wagner","year":"2009","journal-title":"Nat. Rev. Cancer"},{"key":"ref_134","doi-asserted-by":"crossref","unstructured":"Wang, W.-R., Yan, L., Zhao, C.-Y., He, C.-C., and Gao, X.-H. (2026). Glycolytic reprogramming and immune responses in macrophages: A crosstalk driven by bacterial infection. Front. Immunol., 17.","DOI":"10.3389\/fimmu.2026.1783266"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"3559","DOI":"10.4161\/cc.21572","article-title":"Toll-like receptors, signaling adapters and regulation of the pro-inflammatory response by PI3K","volume":"11","author":"Troutman","year":"2012","journal-title":"Cell Cycle"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"435","DOI":"10.2165\/11588310-000000000-00000","article-title":"Establishment of a Database of Metformin Plasma Concentrations and Erythrocyte Levels in Normal and Emergency Situations","volume":"31","author":"Lalau","year":"2011","journal-title":"Clin. Drug Investig."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"3993","DOI":"10.18632\/aging.102787","article-title":"Metformin: Current clinical applications in nondiabetic patients with cancer","volume":"12","author":"Chen","year":"2020","journal-title":"Aging"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"1543","DOI":"10.1053\/j.gastro.2017.12.040","article-title":"High Accumulation of Metformin in Colonic Tissue of Subjects With Diabetes or the Metabolic Syndrome","volume":"154","author":"Paleari","year":"2018","journal-title":"Gastroenterology"},{"key":"ref_139","doi-asserted-by":"crossref","unstructured":"Li, M., Wei, J., Xue, C., Zhou, X., Chen, S., Zheng, L., Duan, Y., Deng, H., Xiong, W., and Tang, F. (2023). Dissecting the roles and clinical potential of YY1 in the tumor microenvironment. Front. Oncol., 13.","DOI":"10.3389\/fonc.2023.1122110"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"117468","DOI":"10.1016\/j.biopha.2024.117468","article-title":"Unveiling the antitumor synergy between pazopanib and metformin on lung cancer through suppressing p-Akt\/ NF-\u03baB\/ STAT3\/ PD-L1 signal pathway","volume":"180","author":"Abdallah","year":"2024","journal-title":"Biomed. Pharmacother."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1038\/s41586-025-08980-6","article-title":"Mitochondrial metabolism sustains DNMT3A-R882-mutant clonal haematopoiesis","volume":"642","author":"Gozdecka","year":"2025","journal-title":"Nature"},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1016\/j.jhep.2022.03.010","article-title":"Metformin treatment rescues CD8+ T-cell response to immune checkpoint inhibitor therapy in mice with NAFLD","volume":"77","author":"Wabitsch","year":"2022","journal-title":"J. Hepatol."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"112243","DOI":"10.1016\/j.intimp.2024.112243","article-title":"Clinical evidence for the prognostic impact of metformin in cancer patients treated with immune checkpoint inhibitors","volume":"134","author":"Shen","year":"2024","journal-title":"Int. Immunopharmacol."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1093\/jnci\/djae295","article-title":"Obesity-specific improvement of lung cancer outcomes and immunotherapy efficacy with metformin","volume":"117","author":"Smith","year":"2024","journal-title":"JNCI J. Natl. 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