It has become increasingly widely recognized that the stroma plays several vital roles in tumor growth and development and that tumor-stroma interactions can in many cases account poor therapeutic response. Inspired by an emerging body of literature, we consider the potential role of photodynamic therapy (PDT) for targeting interactions with stromal fibroblasts and mechano-sensitive signaling with the extracellular matrix as a means to drive tumors toward a more therapeutically responsive state and synergize with other treatments. This concept is particularly relevant for cancer of the pancreas, which is characterized by tumors with a profoundly dense, rigid fibrous stroma. Here we introduce new in vitro systems to model interactions between pancreatic tumors and their mechanical microenvironment and restore signaling with stromal fibroblasts. Using one such model as a test bed it is shown here that PDT treatment is able to destroy fibroblasts in an in vitro 3D pancreatic tumor-fibroblast co-culture. These results and the literature suggest the further development of PDT as a potential modality for stromal depletion.