DPY30 is an epigenetic decoupler linking replication stress to immunoediting in pancreatic cancer
Perturbations in DNA replication can impair fork stability, resulting in cumulative DNA replication stress. As activation of the DNA stress response elicits immunomodulatory effects, understanding the crosstalk between the epigenetic control of replication fork stability and the recruitment of immune cells may represent an actionable avenue to potentiate the sensitivity of tumors to immunotherapy. Here, we identified DPY30, a member of the histone methyltransferase WRAD/COMPASS complex, as a replication stress-specific epigenetic modifier in pancreatic ductal adenocarcinoma (PDAC). While other WRAD components broadly regulate transcription, DPY30 distinctively promoted H3K4me3 deposition at stressed DNA replication forks to safeguard DNA replication stability without altering global gene expression. Loss of DPY30 destabilized stalled forks causing fork degradation, chromosomal instability, and inflammation without reducing cancer cell proliferation. Consequently, T-cell infiltration induced by DPY30 deficiency promoted a tumor response to immune checkpoint blockade (ICB). In PDAC patients, high DPY30 tumor expression was associated with poorer ICB response, underscoring the potential of DPY30 as a predictive biomarker of immunotherapy response. Together, this study redefines our understanding of a replication stress-specific epigenetic code, unveiling DPY30 as a chromatin switch essential for stressed fork stability and a potential therapeutic target.
Authors
- Mauro Di Pilato (ORCID: https://orcid.org/0000-0003-3902-7406)
- Collene Jeter (ORCID: https://orcid.org/0000-0002-9627-4529)
- Katharina Schlacher (ORCID: https://orcid.org/0000-0001-7226-6391)
- Malgorzata Anna Zal (ORCID: https://orcid.org/0000-0002-1015-3954)
- Sunetra Roy
- Francesca Citron (ORCID: https://orcid.org/0000-0002-5896-3008)
- Yonathan Lissanu (ORCID: https://orcid.org/0000-0003-1024-5303)
- Er-Yen Yen (ORCID: https://orcid.org/0000-0003-2918-5419)
- Charles A. Dyke (ORCID: https://orcid.org/0009-0007-5431-5445)
- Ko‐Chien Chen (ORCID: https://orcid.org/0000-0001-5480-3683)
- Sisi Gao (ORCID: https://orcid.org/0000-0002-4809-1699)
- Luigi Perelli (ORCID: https://orcid.org/0000-0001-7320-8193)
- Virginia Giuliani (ORCID: https://orcid.org/0000-0002-2439-4986)
- Chiara Balestrieri (ORCID: https://orcid.org/0000-0001-7362-3530)
- Giulio Draetta (ORCID: https://orcid.org/0000-0001-5225-9610)
- Maria Chiara Bonini
- Nicholas Blazanin (ORCID: https://orcid.org/0009-0000-4171-1624)
- Giannicola Genovese (ORCID: https://orcid.org/0000-0003-1392-9954)
- Giovanni Tonon (ORCID: https://orcid.org/0000-0003-2973-5038)
- Alessandro Carugo
- Elisabetta Granato (ORCID: https://orcid.org/0000-0002-7207-5832)
- Hyuk Jean Kwon (ORCID: https://orcid.org/0009-0000-7055-0014)
- Luca Cecchetto (ORCID: https://orcid.org/0000-0001-9746-639X)
- I-Lin Ho (ORCID: https://orcid.org/0000-0002-8914-710X)
- Timothy P. Heffernan (ORCID: https://orcid.org/0000-0002-3166-8922)
- Iolanda Scognamiglio (ORCID: https://orcid.org/0000-0003-0276-3207)
- L Wang
- L. Zhang
- Sanjana Srinivasan
- Cecilia S. Leung
- R. S. Shah
- John A Tainer
- Zhaoliang Liu
- Shan Jiang
- Wantong Yao
- Sergio Attanasio
- Yue Chen
- Jing Pan
- Luis A. Castillo Montanez
- Andrea Viale
- Ziheng Chen
Institutions
- The University of Texas MD Anderson Cancer Center (US)
- Vita-Salute San Raffaele University (IT)
- IRCCS Ospedale San Raffaele (IT)
- IRBM Science Park (IT)
Publication Details
- Journal
- Cancer Research
- Published
- 2026-04-06
- DOI
- https://doi.org/10.1158/0008-5472.can-25-3849
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 0.00