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

  • Cell Rep. 2025 Sep 24;44(10):116347. doi: 10.1016/j.celrep.2025.116347.
Maria Korah  1 ,  Rosyli F Reveron-Thornton  1 ,  Mahsa Fallah  1 ,  Peter Y Xie  2 ,  Amanda Gonçalves  1 ,  Chuner Guo  1 ,  James P Agolia  1 ,  Andrea E Delitto  1 ,  Renceh A B Flojo  3 ,  Biren Reddy  4 ,  Kaylin A Yip  4 ,  John M Lu  1 ,  Antonio Tomasso  4 ,  Angela D Tabora  1 ,  Jason L Guo  1 ,  Khristian E Bauer-Rowe  1 ,  Benjamin Pham  4 ,  Lipika Goyal  5 ,  Amanda R Kirane  3 ,  Gregory W Charville  6 ,  Ovijit Chaudhuri  7 ,  Monica M Dua  3 ,  Brendan C Visser  3 ,  Byrne Lee  3 ,  George A Poultsides  3 ,  Derrick C Wan  1 ,  Jeffrey A Norton  1 ,  Deshka S Foster  1 ,  Michael T Longaker  1 ,  Daniel Delitto  8
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: [email protected].
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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