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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 reports Korah, M., Reveron-Thornton, R. F., Fallah, M., Xie, P. Y., Gonçalves, A., Guo, C., Agolia, J. P., Delitto, A. E., Flojo, R. A., Reddy, B., Yip, K. A., Lu, J. M., Tomasso, A., Tabora, A. D., Guo, J. L., Bauer-Rowe, K. E., Pham, B., Goyal, L., Kirane, A. R., Charville, G. W., Chaudhuri, O., Dua, M. M., Visser, B. C., Lee, B., Poultsides, G. A., Wan, D. C., Norton, J. A., Foster, D. S., Longaker, M. T., Delitto, D. 2025; 44 (10): 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.

View details for DOI 10.1016/j.celrep.2025.116347

View details for PubMedID 41004339