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Here, we investigated the biological and clinical significance of myeloid\u2010derived growth factor (MYDGF) through an integrative strategy spanning single\u2010cell profiling, bulk multiomics, and functional validation. Analysis of scRNA\u2010seq data (GSE156632) revealed that MYDGF is preferentially detected in malignant epithelial subpopulations and associated with the composition of myeloid and lymphoid compartments. Integration with TCGA\u2010KIRC transcriptomic and clinical datasets demonstrated strong associations between MYDGF expression and immune\u2010checkpoint activation, immune dysfunction signatures, and PI3K\/AKT\u2013MAPK pathway activity. Tumors with high MYDGF expression exhibited an immune\u2010infiltrated yet functionally impaired microenvironment and were predicted to show reduced responsiveness to immune checkpoint blockade. Differential expression and enrichment analyses further highlighted MYDGF\u2010associated genes involved in inflammatory, extracellular, and receptor\u2010binding functions. A machine learning pipeline using LASSO Cox regression identified a preliminary 19\u2010gene MYDGF\u2010related prognostic gene set that requires further validation. Functional experiments confirmed that MYDGF knockdown suppressed proliferation, migration, and invasion in ccRCC cells. Overall, our analyses characterize MYDGF as a microenvironment\u2010related biomarker linked to immune\u2010associated features, signaling\u2010associated alterations, and adverse prognosis in ccRCC. These results nominate MYDGF as a candidate prognostic biomarker and show the value of pairing single\u2010cell resolution with computational modeling for biomarker discovery in renal cancer.<\/jats:p>","DOI":"10.1155\/humu\/5262666","type":"journal-article","created":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T07:41:18Z","timestamp":1784965278000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Single\u2010Cell and Machine Learning Analyses Identify MYDGF as an Immune\u2010Related Biomarker Associated With the Tumor Microenvironment in Clear Cell Renal Cell Carcinoma"],"prefix":"10.1155","volume":"2026","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0100-9117","authenticated-orcid":false,"given":"Yingkun","family":"Xu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guandu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinxiu","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaochen","family":"Qi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9007-151X","authenticated-orcid":false,"given":"Guangzhen","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,25]]},"reference":[{"key":"e_1_2_15_1_2","doi-asserted-by":"publisher","DOI":"10.3390\/cancers15030665"},{"key":"e_1_2_15_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41581-020-0316-3"},{"key":"e_1_2_15_3_2","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-17-1299"},{"key":"e_1_2_15_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2021.02.015"},{"key":"e_1_2_15_5_2","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13225856"},{"key":"e_1_2_15_6_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24097946"},{"key":"e_1_2_15_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2021.02.013"},{"key":"e_1_2_15_8_2","doi-asserted-by":"publisher","DOI":"10.1186\/s10020-024-00874-z"},{"key":"e_1_2_15_9_2","doi-asserted-by":"publisher","DOI":"10.7150\/thno.49327"},{"key":"e_1_2_15_10_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jproteome.5c00385"},{"key":"e_1_2_15_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.05.031"},{"key":"e_1_2_15_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.04.048"},{"key":"e_1_2_15_13_2","doi-asserted-by":"publisher","DOI":"10.15252\/msb.20188746"},{"key":"e_1_2_15_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-019-0619-0"},{"key":"e_1_2_15_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-018-0276-y"},{"key":"e_1_2_15_16_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-17-0307"},{"key":"e_1_2_15_17_2","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1007\/978-1-4939-7493-1_12","volume-title":"Cancer 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