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This study aims to systematically elucidate the molecular mechanisms underlying irinotecan resistance in colorectal cancer (CRC) by constructing patient\u2010derived organoid (PDO) models combined with single\u2010cell transcriptomics technology.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>PDO models were successfully established from irinotecan\u2010resistant and sensitive CRC patients. Single\u2010cell RNA sequencing (scRNA\u2010seq) was performed on the organoids, analyzing the transcriptomic heterogeneity of 12,360 high\u2010quality cells. Gene Set Variation Analysis (GSVA), transcriptional regulatory networks, and cell communication networks were employed to dissect the resistance mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Drug sensitivity assays demonstrated that the IC\n                      <jats:sub>50<\/jats:sub>\n                      value of irinotecan in CRC5 was significantly higher than that in CRC11, which was entirely consistent with their respective clinical phenotypes. Single\u2010cell sequencing identified CRC5\u2010specific drug\u2010resistant cell clusters, Cluster 1 and Cluster 6. Cluster 1 (MARCKSL1+) was characterized by the activation of the Wnt signaling pathway and extracellular matrix (ECM) remodeling, which collectively contributed to the maintenance of stem cell\u2010like properties, while Cluster 6 (AKR1C3+) exhibited significant enrichment in lipid metabolism and the Notch signaling pathway.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study integrates PDO models with single\u2010cell transcriptomics technology to reveal key cell subpopulations and molecular mechanisms underlying irinotecan resistance. The core mechanisms driving resistance involve the activation of Wnt signaling and the synergistic effect of lipid metabolism\u2010Notch pathways. Cluster 1 and Cluster 6 are identified as potential therapeutic targets, providing a theoretical basis for developing combination therapies targeting cancer stem cells or the metabolic microenvironment.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cam4.71550","type":"journal-article","created":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T18:10:29Z","timestamp":1770919829000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Colorectal Cancer Organoid Model Reveals the Mechanisms of Irinotecan Resistance at Single\u2010Cell Resolution"],"prefix":"10.1002","volume":"15","author":[{"given":"Yi","family":"Pan","sequence":"first","affiliation":[{"name":"Central Laboratory and Precision Medicine Center, Affiliated Jinhua Hospital Zhejiang University School of Medicine  Jinhua Zhejiang Province China"},{"name":"Jinhua Key Laboratory of Cancer Nutrition and Metabolism Research, Affiliated Jinhua Hospital 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