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This study identifies the histone demethylase KDM6B as a key regulator of myeloid\u2010derived suppressor cells (MDSCs) recruitment in CRC. Intestinal epithelial\u2010specific KDM6B deletion promotes tumor growth by increasing MDSCs\u2010mediated immunosuppression. Mechanistically, KDM6B directly transcriptionally activates solute carrier family 10 member 2 (SLC10A2),\u00a0whereas its loss increased H3K27me3 repression at the SLC10A2 promoter, activating the ERK\/AP\u20101 pathway and subsequent CXCL\/CXCR2\u2010dependent MDSC recruitment. Clinically, KDM6B expression positively correlated with SLC10A2 levels and inversely correlated with MDSC infiltration in human CRC specimens. More importantly, KDM6B knockdown conferred resistance to anti\u2010PD\u20101 therapy in CRC, whereas its overexpression synergized with anti\u2010PD\u20101 therapy. In conclusion, this study establishes the KDM6B\u2013SLC10A2 axis as a novel epigenetic immune checkpoint, highlighting its potential as a therapeutic target for reprogramming the immunosuppressive microenvironment in CRC.<\/jats:p>","DOI":"10.1002\/advs.202514086","type":"journal-article","created":{"date-parts":[[2025,12,13]],"date-time":"2025-12-13T02:19:24Z","timestamp":1765592364000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The KDM6B\/SLC10A2 Axis Suppresses MDSCs Recruitment via ERK\/AP\u20101 Signaling in Colorectal Cancer"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4462-1824","authenticated-orcid":false,"given":"Zhibo","family":"Hu","sequence":"first","affiliation":[{"name":"Tianjin Nankai Hospital Tianjin Medical University; Institute of Integrative Medicine for Acute Abdominal Diseases Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair  Tianjin 300100 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Xun","sequence":"additional","affiliation":[{"name":"Tianjin Nankai Hospital Tianjin Medical University; 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