Pancreatic ductal adenocarcinoma (PDA) is an aggressive cancer with particularly poor clinical outcomes, in part, because of a dramatically altered stromal environment and striking immune dysfunction. Physical properties within tumors— such as aligned fiber architectures—are fundamental to cancer progression and invasion, and negatively correlate with survival in cancers like those of the breast. However, the influence of aligned architectures in PDA remains unexplored. Here, we elucidate the role extracellular matrix alignment has in establishing an immunosuppressive, metastasis-conducive tumor microenvironment in early, preinvasive PDA, as well as in precursory pancreatic inflammation. Using both mouse and human samples, we demonstrate an inextricable link between collagen, alignment, and 1) immunosuppressive macrophage localization, phenotype, and function (Chapter 2);​ 2) epithelial cell extrusion and subsequent invasion from intact ductal structures (Chapter 3). The contribution of alignment in both driving macrophage polarization and tumor cell dissemination could be attributed to altered focal adhesion dynamics, as targeting FAK in vivo resulted in a concomitant decrease in aligned collagen architectures, disseminated tumor cells, metastatic burden, and elongated, immunosuppressive macrophages. In Chapter 4, we explore the interplay between macrophages, collagen, and cancer cell extrusion using novel 3D microtissue co-cultures and human biopsies to reveal contributions of macrophages to dissemination in vitro and in vivo. Importantly, we show aligned collagen signatures and immunosuppressive macrophages are abundantly prevalent in pancreatitis, a known risk factor for PDA, suggesting that pancreatic precursory disease may create stromal memory that is later conducive to early immunosuppression and dissemination of PDA. This work highlights the opportunity to utilize FAK inhibitors to target stromal immunity and architectures and supports a model in which collagen architecture drives the early involution of an immunosuppressive, malignant microenvironment. Further, this thesis underscores the importance of targeting stromal matrices in precursor inflammation, limit cancer progression, and “reprogram” stromal immunity