Abstract Pancreatic ductal adenocarcinoma (PDAC) is remarkably resistant to immunotherapy. We previously described a tumor-liver axis in which PDAC drives STAT3 signaling in hepatocytes, inducing liver inflammation that promotes liver metastasis and tumor T cell exclusion. Here, we investigated how hepatocyte STAT3 signaling-induced liver inflammation affects response to immunotherapy. Orthotopic and subcutaneous PDAC mouse models were used to study tumor-induced STAT3 signaling in the liver. IL6-induced STAT3 signaling in hepatocytes was achieved via hydrodynamic tail vein injections of an IL6 plasmid or IV injections of AAV8 expressing IL6 under a hepatocyte-specific promotor (AAV-TBG-IL6). Anti-IL6 receptor (aIL6R) was used for global inhibition of IL6 signaling. Hepatocyte-specific STAT3 knockout was achieved in Stat3flox/flox mice using IV injections of AAV8-TBG-Cre or by crossing with Albumin-Cre+/+ mice (CKO). To assess immunotherapy response, mice were treated with Dectin-1 and anti-CD40 agonists (BG/CD40). Orthotopic implantation of PDAC tumors increased serum IL6 concentrations (0. 0 vs 339 pg/mL, P=0. 03) and hepatic pSTAT3 compared to controls (40 vs 2550 pSTAT3+ cells/mm2, P=0. 01). Expression of liver inflammatory genes (Saa1, Saa2, Lcn2, Fn1, Ccl6) and serum SAA concentrations were also elevated (7. 7 vs 0. 0 mg/mL, P=0. 02). In non-tumor-bearing mice, IL6 expression induced liver inflammatory genes to levels comparable to tumor-bearing mice, confirming IL6 sufficiency in driving liver inflammation. Pre-treatment with aIL6R prior to tumor implantation inhibited liver inflammatory gene expression and serum SAA concentrations (2. 1 vs 0. 1 mg/mL, P=0. 05). However, treatment with aIL6R after tumor implantation only modestly reduced some liver inflammatory gene expression, and serum SAA was not significantly reduced (2. 1 vs 1. 6 mg/mL, P=0. 4), suggesting IL6 inhibition is not capable of reversing established liver inflammation. In contrast, hepatocyte-specific STAT3 deletion via AAV8-TBG-Cre after tumor implantation reduced liver inflammation gene expression to levels similar to pre-treated mice and reversed serum SAA levels (8. 2 vs 0. 7 mg/mL, P=0. 04). Immunohistochemistry confirmed hepatic pSTAT3 was reduced (4711 vs 2070 pSTAT3+ cells/mm2, P=0. 05) with no significant change in tumor or spleen pSTAT3. To test the effect of hepatocyte STAT3 signaling on immunotherapy, CKO or wild-type mice were pretreated with AAV-TBG-IL6 and then implanted with PDAC tumors. Fourteen days later, mice received placebo or BG/CD40. Wild-type mice had similar tumor growth and survival regardless of treatment (median survival: 50 vs 50 days, P=NS). In contrast, CKO mice treated with BG/CD40 showed slower tumor growth and improved survival compared to placebo (median survival: 50 vs 79 days, P0. 001). These findings highlight hepatocyte IL6-STAT3 signaling as a key driver of liver inflammation that undermines immunotherapy efficacy in PDAC. Additionally, this study supports hepatocyte-specific STAT3 signaling as a therapeutic target to modulate immunotherapy responses. Citation Format: John C. McVey, Heather Coho, Anna S. Thickens, Kayjana Coho, Yan Li, Prithvi Parthasarathy, Priscilla S. Chan, Kelly Markowitz, Devora Delman, Meredith L. Stone, Gregory L. Beatty. Hepatocyte STAT3 signaling drives response to immunotherapy in pancreatic cancer 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 (18Suppl₃): Abstract nr B013.
McVey et al. (Sun,) studied this question.