The KDM6B/SLC10A2 Axis Suppresses MDSCs Recruitment via ERK/AP‐1 Signaling in Colorectal Cancer

Abstract Colorectal cancer (CRC) progression is regulated by an immunosuppressive tumor microenvironment, but the epigenetic mechanisms governing this milieu remain unclear. This study identifies the histone demethylase KDM6B as a key regulator of myeloid‐derived suppressor cells (MDSCs) recruitment in CRC. Intestinal epithelial‐specific KDM6B deletion promotes tumor growth by increasing MDSCs‐mediated immunosuppression. Mechanistically, KDM6B directly transcriptionally activates solute carrier family 10 member 2 (SLC10A2), whereas its loss increased H3K27me3 repression at the SLC10A2 promoter, activating the ERK/AP‐1 pathway and subsequent CXCL/CXCR2‐dependent 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‐PD‐1 therapy in CRC, whereas its overexpression synergized with anti‐PD‐1 therapy. In conclusion, this study establishes the KDM6B–SLC10A2 axis as a novel epigenetic immune checkpoint, highlighting its potential as a therapeutic target for reprogramming the immunosuppressive microenvironment in CRC.