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This study explored how migration and invasion inhibitory protein (MIIP) influences CRC progression by regulating tumor\u2010associated neutrophils (TANs) infiltration and NETs formation. On the basis of bioinformatics analysis and clinical CRC samples, we observed that a high density of neutrophils and a high abundance of NETs were correlated with low MIIP expression in CRC tissue as well as distant metastasis and poor prognosis. In vitro co\u2010culture assays revealed that conditioned medium from CRC cells with downregulated MIIP expression recruited neutrophils to form NETs and that NETs further enhanced the migratory and invasive abilities of CRC cells. Mechanistically, the results of this study demonstrated that MIIP directly bound to Protein Kinase R, which inhibited the Nuclear Factor kappa\u2010B\u00a0pathway and Interleukin \u2010 8\u00a0expression and accordingly suppressed TANs infiltration and NETs formation. In addition, preliminary results from an intrasplenic mouse model of CRC liver metastasis suggested the potential therapeutic significance of Deoxyribonuclease I (DNase I, a NET inhibitor), and MIIP augmented the inhibition of CRC metastasis by DNase I. This study revealed that MIIP is a regulator of CRC cell\u2010neutrophil crosstalk and indicated that NETs are potential therapeutic targets in CRC.<\/jats:p>","DOI":"10.1002\/advs.78063","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:34:36Z","timestamp":1790742876000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["MIIP Inhibits Colorectal Cancer Progression by Modulating Neutrophils Infiltration and Neutrophil Extracellular Trap Formation"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-0602-2230","authenticated-orcid":false,"given":"Jiaxin","family":"Li","sequence":"first","affiliation":[{"name":"Department of Pathology National Clinical Research Center for Cancer Tianjin's Clinical Research Center for Cancer Tianjin Key Laboratory of Digestive Cancer Tianjin Medical University Cancer Institute &amp; Hospital  Tianjin 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