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DPY30 Sticks a Fork in PDAC Immunity

Bhushan L Thakur1, Philipp Oberdoerffer1,2

  • 1Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Cancer Research
|June 15, 2026
PubMed

Insights

Loss of DPY30 in pancreatic cancer enhances antitumor immunity by increasing DNA damage and immune cell infiltration. This finding suggests targeting DPY30 could improve immunotherapy effectiveness in pancreatic ductal adenocarcinoma.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with poor response to immunotherapy.
  • Replication stress and genome instability can activate anti-tumor immunity via the cGAS/STING pathway.
  • Regulators of replication stress may influence immunotherapy outcomes.

Purpose of the Study:

  • To identify regulators of replication stress that impact immune activation in PDAC.
  • To investigate the role of dumpy-30 (DPY30) in PDAC's immune response and sensitivity to immunotherapy.

Main Methods:

  • Investigated the function of DPY30, a component of the WRAD complex and SET1/MLL histone methyltransferases.
  • Assessed the impact of DPY30 loss on replication fork protection, DNA damage, and cGAS/STING pathway activation in PDAC.
  • Evaluated changes in immune cell infiltration, T cell-mediated killing, and immune checkpoint blockade (ICB) response in DPY30-deficient PDAC models.

Main Results:

  • DPY30 loss compromises replication fork protection, leading to DNA damage and robust cGAS/STING activation.
  • DPY30-deficient PDAC tumors exhibit increased immune cell infiltration and enhanced sensitivity to T cell-mediated killing.
  • Inhibition of DPY30 improves the response to immune checkpoint blockade (ICB) in PDAC.
  • DPY30 functions as a replication fork-specific chromatin effector, promoting H3K4 and H3K9 methylation at replication forks.

Conclusions:

  • DPY30 acts as a suppressor of replication stress-induced immune activation in PDAC.
  • Targeting DPY30 can amplify antitumor immunity and potentiate immunotherapy responses in PDAC.
  • DPY30 inhibition offers a potential strategy to overcome resistance to immunotherapy in PDAC and other cancers.

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