Disruption of fibroblast MYD88 signaling promotes antitumor immunity in pancreatic ductal adenocarcinoma

Maria Korah¹, Rosyli F Reveron-Thornton¹, Mahsa Fallah¹, Peter Y Xie², Amanda Gonçalves¹, Chuner Guo¹, James P Agolia¹, Andrea E Delitto¹, Renceh A B Flojo³, Biren Reddy⁴, Kaylin A Yip⁴, John M Lu¹, Antonio Tomasso⁴, Angela D Tabora¹, Jason L Guo¹, Khristian E Bauer-Rowe¹, Benjamin Pham⁴, Lipika Goyal⁵, Amanda R Kirane³, Gregory W Charville⁶, Ovijit Chaudhuri⁷, Monica M Dua³, Brendan C Visser³, Byrne Lee³, George A Poultsides³, Derrick C Wan¹, Jeffrey A Norton¹, Deshka S Foster¹, Michael T Longaker¹, Daniel Delitto⁸

Affiliations

¹ Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA; Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
² Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA; Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Mechanical Engineering, Stanford University, Stanford, CA 94305, USA.
³ Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁴ Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁵ Department of Medical Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁶ Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁷ Department of Mechanical Engineering, Stanford University, Stanford, CA 94305, USA.
⁸ Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA; Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: delitto@stanford.edu.

PMID: 41004339
DOI: 10.1016/j.celrep.2025.116347

Free article

Disruption of fibroblast MYD88 signaling promotes antitumor immunity in pancreatic ductal adenocarcinoma

Maria Korah et al. Cell Rep. 2025.

Free article

. 2025 Oct 28;44(10):116347.

doi: 10.1016/j.celrep.2025.116347. Epub 2025 Sep 24.

Authors

Affiliations

¹ Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA; Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
² Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA; Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Mechanical Engineering, Stanford University, Stanford, CA 94305, USA.
³ Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁴ Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁵ Department of Medical Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁶ Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁷ Department of Mechanical Engineering, Stanford University, Stanford, CA 94305, USA.
⁸ Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA; Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: delitto@stanford.edu.

PMID: 41004339
DOI: 10.1016/j.celrep.2025.116347

Abstract

Pancreatic ductal adenocarcinoma (PDAC) continues to carry a dismal prognosis. The disease is characterized by a uniquely dense fibrotic matrix generated by cancer-associated fibroblasts (CAFs). We have previously demonstrated that fibroblast-driven chronic inflammation suppresses T cell function through a myeloid differentiation primary response protein 88 (MYD88)-dependent mechanism. While extensively studied in myeloid cells, the role of MYD88 signaling in CAFs and its effects on PDAC remain poorly understood. In this study, we identify a MYD88-driven inflammatory CAF population in PDAC using a combination of bulk, single-cell, and spatial transcriptomic studies. Using an innovative collagen gel implantation model, we demonstrate that loss of MYD88 in CAFs enhances T cell infiltration and suppresses tumor growth. Combining MYD88 inhibition with immune checkpoint blockade significantly reduces tumor size and enhances antitumor immune responses, underscoring its potential as a therapeutic target in PDAC.

Keywords: CA-4948; CP: Cancer; CP: Immunology; MYD88; PDAC; cancer-associated fibroblast; immune checkpoint blockade; inflammatory CAF; pancreatic ductal adenocarcinoma.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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Disruption of fibroblast MYD88 signaling promotes antitumor immunity in pancreatic ductal adenocarcinoma

Affiliations

Disruption of fibroblast MYD88 signaling promotes antitumor immunity in pancreatic ductal adenocarcinoma

Authors

Affiliations

Abstract

Conflict of interest statement

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous