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This study investigated the impact of histologically unique activated cancer\u2010associated fibroblasts (aCAFs) on survival outcomes and immune responses and examined their association with various pathophysiological mechanisms. We analyzed a total of 1,024 colorectal adenocarcinoma patients from two cohorts. aCAFs were evaluated based on hematoxylin and eosin\u2010stained whole\u2010slide images, and their associations with clinicopathological features, immune cell infiltration, and survival were assessed. We developed a machine learning\u2010based survival prediction model incorporating aCAFs and clinicopathologic parameters. Additionally, we performed differential gene expression analysis, functional enrichment analyses, and\n                    <jats:italic>in vitro<\/jats:italic>\n                    drug screening of aCAF\u2010related genes. aCAFs were associated with advanced T stage, lymphovascular invasion, perineural invasion, and decreased CD8+ and CD4+ T cell infiltration. aCAFs were also associated with worse overall and disease\u2010free survival in both univariate and multivariate analyses. Functional enrichment analysis revealed that aCAF\u2010related genes were implicated in immunosuppressive signaling, oxidative stress regulation, and tumor progression pathways. Survival prediction models based on machine learning and incorporating aCAFs demonstrated superior prognostic accuracy for overall survival and disease\u2010free survival compared to models excluding aCAFs. Our analysis of aCAFs' association with immune responses through bioinformatics\u2010based genomic analysis and machine learning provides a foundation for future research in CRC patients.\n                  <\/jats:p>","DOI":"10.1002\/2056-4538.70076","type":"journal-article","created":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T05:12:23Z","timestamp":1771823543000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cancer\u2010associated fibroblasts are associated with\n                    <scp>CD8<\/scp>\n                    + T cell depletion and poor prognosis in colorectal adenocarcinoma: a multi\u2010omics and machine learning analysis"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2029-9081","authenticated-orcid":false,"given":"Myungsun","family":"Shim","sequence":"first","affiliation":[{"name":"Department of Urology, Hanyang University Guri Hospital Hanyang 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College of Medicine Hanyang University  Seoul Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7602-7977","authenticated-orcid":false,"given":"Seung Wook","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Urology, Hanyang University Guri Hospital Hanyang University College of Medicine  Guri Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2101-1019","authenticated-orcid":false,"given":"Hong Sang","family":"Moon","sequence":"additional","affiliation":[{"name":"Department of Urology, Hanyang University Guri Hospital Hanyang University College of Medicine  Guri Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5939-2211","authenticated-orcid":false,"given":"Hyung Suk","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Surgery, Hanyang University 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