Oncolytic herpes simplex virus reprograms cancer-associated fibroblasts to enhance antitumor immunity in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) exhibits profound cancer-associated fibroblast (CAF)-driven immunosuppression. While oncolytic herpes simplex virus (oHSV) remodels the tumor microenvironment (TME), its direct impact on CAFs remains unclear. Here, we utilized a CAF-enriched PDAC model (1:10 KPC tumor cells:pancreatic stellate cells) to investigate oHSV therapy. Crucially, oHSV directly infects CAFs, inducing a subtype shift: it reduces immunosuppressive myofibroblastic CAFs and increases antigen-presenting CAFs. Mechanistically, oHSV upregulated major histocompatibility complex class I (MHC class I), MHC class II, and CD86 expression on CAFs; enhanced T cell activation; and significantly decreased regulatory T cells (Tregs). Furthermore, oHSV-infected CAFs boosted neutrophil recruitment and activation. Collectively, oHSV-mediated CAF reprogramming reshaped the immune landscape by reducing immunosuppression and enhancing both innate and adaptive anti-tumor immunity. This resulted in delayed tumor progression in the CAF-rich model, highlighting oHSV as a promising strategy to overcome the immunosuppressive TME in PDAC.