{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Shen C"],"funding":["National Natural Science Foundation of China"],"pagination":["12867-12880"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11798317"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["149(14)"],"pubmed_abstract":["<h4>Purpose</h4>Immunotherapy with programmed cell death 1/ligand 1 (PD-1/PD-L1) checkpoint inhibitors has revolutionized the systemic treatment of solid tumors, including bladder cancer. Previous studies have shown that enhanced glycolysis, tumor-associated macrophage (TAM) infiltration, and TGF-β secretion in the tumor microenvironment (TME) are closely related to PD-1/PD-L1 inhibitor immunotherapy resistance. However, the potential mechanism of their interaction in bladder cancer has not been fully uncovered.<h4>Methods</h4>By coculturing bladder cancer cells and TAMs, we studied the relationship and interaction mechanism between tumor cell glycolysis, TAM functional remodeling, TGF-β positive feedback secretion, and PD-L1 mRNA m6A methylation in the bladder cancer microenvironment.<h4>Results</h4>Bioinformatics analysis and IHC staining found a close correlation between tumor glycolysis, M2 TAM infiltration, and the prognosis of bladder cancer patients. In Vitro experiments demonstrated that bladder cancer cells could re-educate M2 TAMs through lactate and promote TGF-β secretion via the HIF-1α signaling pathway. Reciprocally, in vitro, and in vivo experiments validated that M2 TAMs could promote glycolysis in bladder cancer cells by TGF-β via the Smad2/3 signaling pathways. Furthermore, M2 TAMs could also promote CSCs and EMT of bladder cancer cells. More importantly, we found M2 TAMs enhance PD-L1 mRNA m6A methylation by promoting METLL3 expression in bladder cancer via the TGF-β/Smad2/3 pathway in the TME.<h4>Conclusions</h4>Our study highlights a feed-forward loop based on aerobic glycolysis and TGF-β between M2 TAMs and bladder cancer cells, which may be a potential mechanism of malignant progression and immunotherapy resistance in bladder cancer."],"journal":["Journal of cancer research and clinical oncology"],"pubmed_title":["A feed-forward loop based on aerobic glycolysis and TGF-β between tumor-associated macrophages and bladder cancer cells promoted malignant progression and immune escape."],"pmcid":["PMC11798317"],"funding_grant_id":["81972378"],"pubmed_authors":["Yang X","Liu J","Zhang X","Shen C","Wang Y","Jiao W","Zhao X"],"additional_accession":[]},"is_claimable":false,"name":"A feed-forward loop based on aerobic glycolysis and TGF-β between tumor-associated macrophages and bladder cancer cells promoted malignant progression and immune escape.","description":"<h4>Purpose</h4>Immunotherapy with programmed cell death 1/ligand 1 (PD-1/PD-L1) checkpoint inhibitors has revolutionized the systemic treatment of solid tumors, including bladder cancer. Previous studies have shown that enhanced glycolysis, tumor-associated macrophage (TAM) infiltration, and TGF-β secretion in the tumor microenvironment (TME) are closely related to PD-1/PD-L1 inhibitor immunotherapy resistance. However, the potential mechanism of their interaction in bladder cancer has not been fully uncovered.<h4>Methods</h4>By coculturing bladder cancer cells and TAMs, we studied the relationship and interaction mechanism between tumor cell glycolysis, TAM functional remodeling, TGF-β positive feedback secretion, and PD-L1 mRNA m6A methylation in the bladder cancer microenvironment.<h4>Results</h4>Bioinformatics analysis and IHC staining found a close correlation between tumor glycolysis, M2 TAM infiltration, and the prognosis of bladder cancer patients. In Vitro experiments demonstrated that bladder cancer cells could re-educate M2 TAMs through lactate and promote TGF-β secretion via the HIF-1α signaling pathway. Reciprocally, in vitro, and in vivo experiments validated that M2 TAMs could promote glycolysis in bladder cancer cells by TGF-β via the Smad2/3 signaling pathways. Furthermore, M2 TAMs could also promote CSCs and EMT of bladder cancer cells. More importantly, we found M2 TAMs enhance PD-L1 mRNA m6A methylation by promoting METLL3 expression in bladder cancer via the TGF-β/Smad2/3 pathway in the TME.<h4>Conclusions</h4>Our study highlights a feed-forward loop based on aerobic glycolysis and TGF-β between M2 TAMs and bladder cancer cells, which may be a potential mechanism of malignant progression and immunotherapy resistance in bladder cancer.","dates":{"release":"2023-01-01T00:00:00Z","publication":"2023 Nov","modification":"2025-08-31T03:13:58.096Z","creation":"2025-08-31T03:05:33.734Z"},"accession":"S-EPMC11798317","cross_references":{"pubmed":["37462772"],"doi":["10.1007/s00432-023-05164-5"]}}