2. Academic Validation
  3. Disruption of fibroblast MYD88 signaling promotes antitumor immunity in pancreatic ductal adenocarcinoma

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

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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