Work

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

Year: 2025

Type: article

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.

Source: Advanced Science

DOI: 10.1002/advs.202514086