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However, the molecular associations linking insomnia-related features to colorectal cancer (CRC), particularly with respect to tumor biology, immune microenvironmental states, and therapy-relevant phenotypes, remain largely unexplored. Multi-omics integration of genomic, transcriptomic, and microbiome data from 3,026 CRC patients across seven independent cohorts, including a large, well-annotated Clinical Omics study of Colorectal Cancer in China (COCC) cohort, enabled insomnia-based molecular classification through unsupervised non-negative matrix factorization (NMF) clustering. The insomnia subtype (IS) was biologically characterized via pathway enrichment, immune deconvolution, microbial profiling, and single-cell transcriptomics. Furthermore, an insomnia score (ISscore) was developed and validated in multiple cohorts for risk stratification and assessment of treatment-response-related indicators in CRC. Unsupervised clustering revealed two distinct molecular subtypes (IS1\/IS2), with IS2 demonstrating significantly poorer survival. IS2 exhibited marked activation of EMT\/angiogenesis pathways versus cell cycle activation in IS1. The IS2 microenvironment showed increased immunosuppression-related infiltration and exhausted T cell signatures, together with intratumoral microbiome variation characterized by depletion of Ruminococcaceae UCG-002 and enrichment of Hungatella\/Selenomonas. The ISscore system stratified survival risk and was associated with computational indicators of immunotherapy response. Single-cell analysis nominated PPIA-BSG as a potential cell-cell communication signal involving high-ISscore tumor cells, CXCL12+ endothelial cells, and CLEC9A+ dendritic cell subsets. This multi-omics characterization of insomnia-CRC interplay suggests that insomnia-related molecular features are associated with an immunologically distinct and microbiome-altered tumor ecosystem. The ISscore provides a reproducible framework for capturing insomnia-related molecular heterogeneity, supporting risk stratification and future evaluation of therapy-relevant phenotypes.<\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>Chronic insomnia affects millions, but it is not typically considered a cancer risk factor. Our study, analyzing vast biological data from over 3,000 colorectal cancer patients, uncovers a potential link between a person\u2019s predisposition to insomnia and their risk of developing this disease. This suggests that the biological pathways related to sleep may play a role in cancer development. Understanding this connection opens up new avenues for identifying individuals at higher risk and developing novel prevention strategies for colorectal cancer.<\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.00815-26","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T13:00:20Z","timestamp":1788958820000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Integrative multi-omics profiling of insomnia-related molecular features reveals microbiome, immune, and therapy-relevant heterogeneity in colorectal cancer"],"prefix":"10.1128","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-9475-9493","authenticated-orcid":true,"given":"Yinmeng","family":"Zhang","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00js3aw79","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of 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