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

Zhibo Hu1, Jing Xun1, Bin Liu1

  • 1Tianjin 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.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|December 12, 2025
PubMed

Insights

The histone demethylase KDM6B regulates myeloid-derived suppressor cells (MDSCs) in colorectal cancer (CRC). Targeting the KDM6B-SLC10A2 axis may reprogram the tumor microenvironment and improve immunotherapy response.

Area of Science:

  • Epigenetics
  • Cancer Immunology
  • Molecular Biology

Background:

  • Colorectal cancer (CRC) progression involves an immunosuppressive tumor microenvironment.
  • Epigenetic mechanisms controlling this microenvironment are not fully understood.

Purpose of the Study:

  • To identify epigenetic regulators of the immunosuppressive tumor microenvironment in CRC.
  • To investigate the role of KDM6B in myeloid-derived suppressor cells (MDSCs) recruitment and CRC progression.

Main Methods:

  • Utilized genetically modified mouse models with intestinal epithelial-specific KDM6B deletion.
  • Performed mechanistic studies involving gene expression analysis, chromatin immunoprecipitation (ChIP), and pathway activation assays.
  • Analyzed human CRC specimens for correlations between KDM6B, SLC10A2, and MDSC infiltration.
  • Evaluated the impact of KDM6B modulation on anti-PD-1 therapy response in CRC models.

Main Results:

  • KDM6B deletion in intestinal epithelium promoted CRC growth by increasing MDSC-mediated immunosuppression.
  • KDM6B directly activates SLC10A2 transcription; its loss leads to H3K27me3 repression at the SLC10A2 promoter.
  • This mechanism activates the ERK/AP-1 pathway, driving CXCL/CXCR2-dependent MDSC recruitment.
  • KDM6B expression positively correlates with SLC10A2 and inversely with MDSC infiltration in human CRC.
  • KDM6B knockdown caused resistance to anti-PD-1 therapy, while overexpression synergized with it.

Conclusions:

  • The KDM6B-SLC10A2 axis is identified as a key epigenetic regulator of MDSC recruitment in CRC.
  • This axis represents a novel epigenetic immune checkpoint.
  • Targeting the KDM6B-SLC10A2 axis holds potential for reprogramming the CRC immunosuppressive microenvironment and enhancing immunotherapy efficacy.
Keywords:
colorectal cancerimmunosuppressivelysine‐specific demethylase 6B (KDM6B)myeloid‐derived suppressor cells (MDSCs)solute carrier family 10 member 2 (SLC10A2)

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