Transcription factor (TF) STAT3 contributes to pancreatic cancer progression through its regulatory roles in both tumor cells and the tumor microenvironment (TME). In this study, we performed a systematic analysis of all TFs in patient-derived gene expression datasets and confirmed STAT3 as a critical regulator in the pancreatic TME. Importantly, we developed a novel framework that is based on TF target gene expression to distinguish between environmental- and tumor-specific STAT3 activities in gene expression studies. Using this framework, our results novelly showed that compartment-specific STAT3 activities, but not STAT3 mRNA, have prognostications towards clinical values within pancreatic cancer datasets. In addition, high TME-derived STAT3 activity correlates with an immunosuppressive TME in pancreatic cancer, characterized by CD4 T cell and monocyte infiltration and high copy number variation burden. Where environmental-STAT3 seemed to play a dominant role at primary pancreatic sites, tumor-specific STAT3 seemed dominant at metastatic sites where its high activity persisted. In conclusion, by combining compartment-specific inference with other tumor characteristics, including copy number variation and immune-related gene expression, we demonstrate our method's utility as a tool to generate novel hypotheses about TFs in tumor biology.