Esophageal cancer is one of the top reasons for cancer-related deaths worldwide, and esophageal squamous cell carcinoma (ESCC) accounts for up to 90% of all esophageal cancer cases. One of the major reasons for the high mortality rate is the lack of targeted therapies for ESCC, particularly for advanced stage disease. The tumor microenvironment (TME) is a complex system of multiple cell types (fibroblasts, immune cells, blood and lymphatic vessels, etc.) that supports tumor growth in various ways. We aimed to investigate some of the mechanisms of dynamic interaction between tumor cells and TME components and to identify approaches to targeting these interactions therapeutically. Desmoplasia, or deposition of connective tissue components (fibroblasts and extracellular matrix (ECM)), is a pronounced histological feature of ESCC. Previous research from the Rustgi lab and others has underscored the importance of cancer-associated fibroblasts (CAFs) and ECM components for ESCC progression. We have identified two cytokines that mediate these effects: IL-6 and RANTES. Through in vitro studies we have confirmed the relevance of these cytokines to human ESCC and determined that they function mostly through activation of STAT3 and ERK1/2 signaling pathways. We have also validated IL-6 and RANTES as novel targets for ESCC therapy by using tocilizumab (human IL-6R antibody) and maraviroc (CCR5 inhibitor) to inhibit the growth of subcutaneous ESCC xenotransplants in vivo. Chronic inflammation and immunosuppressive microenvironment are also essential contributors to ESCC pathogenesis. We have identified the ectoenzyme-receptor CD38 as a driver of expansion of myeloid-derived suppressor cells in several murine models of ESCC. We have also identified six cytokines (IFNγ, TNFα, CXCL16, IGFBP-3, IL-6 and RANTES) as promoters of CD38 expression by these cells in vitro. To determine whether CD38 is a valuable target for therapy, we have utilized a neutralizing antibody to CD38 to suppress tumor growth in a syngeneic murine model of ESCC. In summary, we have identified novel mechanisms of interaction between tumor cells, CAFs and myeloid-derived suppressor cells in esophageal TME. Furthermore, we have tested three independent in vivo approaches to therapeutic targeting of these mechanisms that can potentially improve the clinical outcomes of ESCC treatment.