{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T16:15:39Z","timestamp":1753892139577,"version":"3.41.2"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,6,22]],"date-time":"2023-06-22T00:00:00Z","timestamp":1687392000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> ACSMs play critical roles in lipid metabolism; however, their immunological function within the tumor microenvironment (TME) remains unclear, especially that of ACSM6. In this study, we investigate the latent effect of ACSM6 on bladder cancer (BLCA).<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> Several real-world cohorts, including the Xiangya (in-house), The Cancer Genome Atlas (TCGA-BLCA), and IMvigor210 cohorts, with TCGA-BLCA cohort serving as the discovery cohort were compared. We investigated the potential immunological effects of ACSM6 in regulating the BLCA tumor microenvironment by analyzing its correlation with immunomodulators, anti-cancer immune cycles, immune checkpoints, tumor-infiltrating immune cells, and the T-cell inflamed score (TIS). Additionally, we assessed the precision of ACSM6 in predicting BLCA molecular subtypes and responses to several treatments using ROC analysis. To ensure the robustness of our findings, all results were confirmed in two independent external cohorts: the IMvigor210 and Xiangya cohorts.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> ACSM6 expression was markedly upregulated in BLCA. Our analysis suggests that ACSM6 might have significant impact to promote the formation of a non-inflamed tumor microenvironment because of its negative correlation with immunomodulators, anticancer immune cycles, immune checkpoints, tumor-infiltrating immune cells, and the T-cell inflamed score (TIS). Additionally, high ACSM6 expression levels in BLCA may predict the luminal subtype, which is typically associated with resistance to chemotherapy, neoadjuvant chemotherapy, and radiotherapy. These findings were consistent across both the IMvigor210 and Xiangya cohorts.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> ACSM6 has the potential to serve as a valuable predictor of the tumor microenvironment phenotypes and treatment outcomes in BLCA, thereby contributing to more precise treatment.<\/jats:p>","DOI":"10.3389\/fphar.2023.1222512","type":"journal-article","created":{"date-parts":[[2023,6,22]],"date-time":"2023-06-22T11:17:48Z","timestamp":1687432668000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["ACSM6 overexpression indicates a non-inflammatory tumor microenvironment and predicts treatment response in bladder cancer: results from multiple real-world cohorts"],"prefix":"10.3389","volume":"14","author":[{"given":"Zhiwei","family":"Li","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yiyan","family":"Yao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tiezheng","family":"Qi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zuowei","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dingshan","family":"Deng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bolong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,6,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2208","DOI":"10.1038\/s41379-020-0563-7","article-title":"A novel prognostic two-gene signature for triple negative breast cancer","volume":"33","author":"Alsaleem","year":"2020","journal-title":"Mod. Pathol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1545","DOI":"10.1038\/s41591-018-0157-9","article-title":"Robust prediction of response to immune checkpoint blockade therapy in metastatic melanoma","volume":"24","author":"Auslander","year":"2018","journal-title":"Nat. Med."},{"key":"B3","doi-asserted-by":"publisher","first-page":"2930","DOI":"10.1172\/JCI91190","article-title":"IFN-\u03b3-related mRNA profile predicts clinical response to PD-1 blockade","volume":"127","author":"Ayers","year":"2017","journal-title":"J. Clin. Invest."},{"key":"B4","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1186\/s13059-016-1113-y","article-title":"Erratum to: Estimating the population abundance of tissue-infiltrating immune and stromal cell populations using gene expression","volume":"17","author":"Becht","year":"2016","journal-title":"Genome Biol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1007\/s10528-009-9273-z","article-title":"Comparative analyses of disease risk genes belonging to the acyl-CoA synthetase medium-chain (ACSM) family in human liver and cell lines","volume":"47","author":"Boomgaarden","year":"2009","journal-title":"Biochem. Genet."},{"key":"B6","doi-asserted-by":"publisher","first-page":"e2207155","DOI":"10.1002\/advs.202207155","article-title":"BCAT2 shapes a noninflamed tumor microenvironment and induces resistance to anti-PD-1\/PD-L1 immunotherapy by negatively regulating proinflammatory chemokines and anticancer immunity","volume":"10","author":"Cai","year":"2023","journal-title":"Adv. Sci. (Weinh)"},{"key":"B7","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1016\/j.eururo.2021.01.032","article-title":"Quality of life after bladder cancer: A cross-sectional survey of patient-reported outcomes","volume":"79","author":"Catto","year":"2021","journal-title":"Eur. Urol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1016\/j.molonc.2009.01.005","article-title":"Molecular characterization of apocrine carcinoma of the breast: Validation of an apocrine protein signature in a well-defined cohort","volume":"3","author":"Celis","year":"2009","journal-title":"Mol. Oncol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"922","DOI":"10.1158\/1078-0432.CCR-20-2275","article-title":"FDA approval summary: Enfortumab vedotin for locally advanced or metastatic urothelial carcinoma","volume":"27","author":"Chang","year":"2021","journal-title":"Clin. Cancer Res."},{"key":"B10","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1016\/j.celrep.2016.12.019","article-title":"Pan-cancer immunogenomic analyses reveal genotype-immunophenotype relationships and predictors of response to checkpoint blockade","volume":"18","author":"Charoentong","year":"2017","journal-title":"Cell. Rep."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.immuni.2013.07.012","article-title":"Oncology meets immunology: The cancer-immunity cycle","volume":"39","author":"Chen","year":"2013","journal-title":"Immunity"},{"key":"B12","doi-asserted-by":"publisher","first-page":"2031","DOI":"10.21037\/tau-20-615","article-title":"Analysis of conventional versus advanced pelvic floor muscle training in the management of urinary incontinence after radical prostatectomy: A systematic review and meta-analysis of randomized controlled trials","volume":"9","author":"Feng","year":"2020","journal-title":"Transl. Androl. Urol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"858479","DOI":"10.3389\/fonc.2022.858479","article-title":"Mitochondria dysfunction-mediated molecular subtypes and gene prognostic index for prostate cancer patients undergoing radical prostatectomy or radiotherapy","volume":"12","author":"Feng","year":"","journal-title":"Front. Oncol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1038\/s41443-020-00364-w","article-title":"Current management strategy of treating patients with erectile dysfunction after radical prostatectomy: A systematic review and meta-analysis","volume":"34","author":"Feng","year":"","journal-title":"Int. J. Impot. Res."},{"key":"B15","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1186\/s13073-019-0638-6","article-title":"Molecular and pharmacological modulators of the tumor immune contexture revealed by deconvolution of RNA-seq data","volume":"11","author":"Finotello","year":"2019","journal-title":"Genome Med."},{"key":"B16","doi-asserted-by":"publisher","first-page":"102187","DOI":"10.1016\/j.ctrv.2021.102187","article-title":"Avelumab first-line maintenance in locally advanced or metastatic urothelial carcinoma: Applying clinical trial findings to clinical practice","volume":"97","author":"Grivas","year":"2021","journal-title":"Cancer Treat. Rev."},{"key":"B17","first-page":"1824","article-title":"Oncogenic ACSM1 in prostate cancer is through metabolic and extracellular matrix-receptor interaction signaling pathways","volume":"12","author":"Guo","year":"2022","journal-title":"Am. J. Cancer Res."},{"key":"B18","doi-asserted-by":"publisher","first-page":"100785","DOI":"10.1016\/j.xcrm.2022.100785","article-title":"Neoadjuvant immunotherapy, chemotherapy, and combination therapy in muscle-invasive bladder cancer: A multi-center real-world retrospective study","volume":"3","author":"Hu","year":"2022","journal-title":"Cell. Rep. Med."},{"key":"B19","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1186\/s12916-021-02163-6","article-title":"5mC regulator-mediated molecular subtypes depict the hallmarks of the tumor microenvironment and guide precision medicine in bladder cancer","volume":"19","author":"Hu","year":"","journal-title":"BMC Med."},{"key":"B20","doi-asserted-by":"publisher","first-page":"3089","DOI":"10.7150\/thno.53649","article-title":"Siglec15 shapes a non-inflamed tumor microenvironment and predicts the molecular subtype in bladder cancer","volume":"11","author":"Hu","year":"","journal-title":"Theranostics"},{"key":"B21","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1186\/s13059-016-1028-7","article-title":"Comprehensive analyses of tumor immunity: Implications for cancer immunotherapy","volume":"17","author":"Li","year":"2016","journal-title":"Genome Biol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"W509","DOI":"10.1093\/nar\/gkaa407","article-title":"TIMER2.0 for analysis of tumor-infiltrating immune cells","volume":"48","author":"Li","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"B23","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1016\/j.jare.2021.11.010","article-title":"Emerging strategies for the improvement of chemotherapy in bladder cancer: Current knowledge and future perspectives","volume":"39","author":"Liu","year":"2022","journal-title":"J. Adv. Res."},{"key":"B24","doi-asserted-by":"publisher","first-page":"725223","DOI":"10.3389\/fimmu.2021.725223","article-title":"A robust hypoxia risk score predicts the clinical outcomes and tumor microenvironment immune characters in bladder cancer","volume":"12","author":"Liu","year":"2021","journal-title":"Front. Immunol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"544","DOI":"10.1038\/nature25501","article-title":"TGF\u03b2 attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells","volume":"554","author":"Mariathasan","year":"2018","journal-title":"Nature"},{"key":"B26","doi-asserted-by":"publisher","first-page":"102000","DOI":"10.1016\/j.ctrv.2020.102000","article-title":"The future of bladder cancer therapy: Optimizing the inhibition of the fibroblast growth factor receptor","volume":"86","author":"Morales-Barrera","year":"2020","journal-title":"Cancer Treat. Rev."},{"key":"B27","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1038\/nmeth.3337","article-title":"Robust enumeration of cell subsets from tissue expression profiles","volume":"12","author":"Newman","year":"2015","journal-title":"Nat. Methods"},{"key":"B28","first-page":"543","article-title":"Downregulation of ACSM3 promotes metastasis and predicts poor prognosis in hepatocellular carcinoma","volume":"7","author":"Ruan","year":"2017","journal-title":"Am. J. Cancer Res."},{"key":"B29","first-page":"5402","article-title":"Genome-wide identification of m6A-associated functional SNPs as potential functional variants for thyroid cancer","volume":"11","author":"Ruan","year":"2021","journal-title":"Am. J. Cancer Res."},{"key":"B30","doi-asserted-by":"publisher","first-page":"5545","DOI":"10.3390\/ijms20225545","article-title":"Sphingosine 1-phosphate (S1P)\/S1P receptor signaling and mechanotransduction: Implications for intrinsic tissue repair\/regeneration","volume":"20","author":"Sassoli","year":"2019","journal-title":"Int. J. Mol. Sci."},{"key":"B31","doi-asserted-by":"publisher","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"B32","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1016\/j.eururo.2014.01.006","article-title":"The economics of bladder cancer: Costs and considerations of caring for this disease","volume":"66","author":"Svatek","year":"2014","journal-title":"Eur. Urol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1016\/j.eururo.2009.06.028","article-title":"Recurrence and progression of disease in non-muscle-invasive bladder cancer: From epidemiology to treatment strategy","volume":"56","author":"van Rhijn","year":"2009","journal-title":"Eur. Urol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"6575","DOI":"10.1158\/0008-5472.CAN-18-0689","article-title":"Tip: A web server for resolving tumor immunophenotype profiling","volume":"78","author":"Xu","year":"2018","journal-title":"Cancer Res."},{"key":"B35","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1007\/s13402-021-00658-1","article-title":"ACSM3 suppresses the pathogenesis of high-grade serous ovarian carcinoma via promoting AMPK activity","volume":"45","author":"Yang","year":"2022","journal-title":"Cell. Oncol. (Dordr)."},{"key":"B36","doi-asserted-by":"publisher","first-page":"175","DOI":"10.3892\/ol.2022.13295","article-title":"KLF10 upregulates ACSM3 via the PI3K\/Akt signaling pathway to inhibit the malignant progression of melanoma","volume":"23","author":"Zhao","year":"2022","journal-title":"Oncol. Lett."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2023.1222512\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,22]],"date-time":"2023-06-22T11:17:54Z","timestamp":1687432674000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2023.1222512\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,22]]},"references-count":36,"alternative-id":["10.3389\/fphar.2023.1222512"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2023.1222512","relation":{},"ISSN":["1663-9812"],"issn-type":[{"type":"electronic","value":"1663-9812"}],"subject":[],"published":{"date-parts":[[2023,6,22]]},"article-number":"1222512"}}