Abstract A103: Targeting STAT3 in cancer-associated fibroblasts reprograms the stroma and enhances CD8+ T cell-mediated immunity in PDAC

Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense fibrotic stroma driven by cancer-associated fibroblasts (CAFs), which promotes immune exclusion and tumor progression. Signal transducer and activator of transcription 3 (STAT3) is frequently upregulated in PDAC and has been shown to drive fibrosis, immune suppression, and resistance to therapy across multiple cell types in the tumor microenvironment. To define the role of fibroblast-intrinsic STAT3 signaling in regulating stromal composition and anti-tumor immunity, we generated a fibroblast-specific STAT3 conditional knockout (KO) mouse model (Col1a1Cre;Stat3fl/fl) and established subcutaneous PDAC tumors. Fibroblast-specific STAT3 deletion (Col1a1;Stat3Δ/Δ) significantly delayed tumor growth and improved survival compared to wild-type (WT) controls (Col1a1;Stat3wt/wt). Histological analysis revealed a significant reduction in the expression of αSMA, PDGFRa/b, and collagen type I, indicating attenuated desmoplasia. Notably, immunofluorescence demonstrated increased infiltration of CD8+ T cells in Col1a1;Stat3 KO tumors, suggesting enhanced immune accessibility. To determine the dependency of this effect on CD8+ T cells, mice were treated with anti-CD8 monoclonal antibody or isotype control. Depletion of CD8+ T cells abrogated the tumor growth delay observed in Col1a1;STAT3 KO mice, indicating that CD8+ T cells mediate this anti-tumor effect. Collectively, these findings demonstrate that fibroblast-intrinsic STAT3 promotes a fibrotic, immune-excluded microenvironment that impairs CD8+ T cell–mediated tumor control in PDAC. Preliminary scRNA-sequencing data from Col1a1;STAT3 WT and KO tumors indicate enrichment of an inflammatory CAF (iCAF) subpopulation in the KO tumors, suggesting remodeling of the CAFs toward a more immunogenic tumor microenvironment. Ongoing experiments include the use of the STAT3 inhibitor TTI-101, currently in clinical trials for patients with advanced solid tumors. Targeting STAT3 signaling within CAFs may represent a novel therapeutic strategy to remodel the tumor stroma and enhance anti-tumor immunity in PDAC. Citation Format: Ioannis Paraskevaidis, Kristianna Kolker, Ning Li, Ben Stanger, Edgar Ben-Josef, Ioannis Verginadis. Targeting STAT3 in cancer-associated fibroblasts reprograms the stroma and enhances CD8+ T cell-mediated immunity in PDAC [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr A103.