Tumors are surrounded and infiltrated by a variety of stromal cell types including fibroblasts, immune cells and vascular endothelial cells, which interact with malignant cells to generate the tumor microenvironment (TME). This complex environment is thought to be regulated by the tumor in order to promote its survival and progression, and thus constitutes a potential target for cancer therapy. However, intercellular communication within the microenvironment is not yet well understood. The current study investigates the mechanism by which cancer and immune cells communicate using an in vitro co-culture model. It is demonstrated that interleukin-6 (IL6), a proinflammatory cytokine, secreted by immune cells promotes colorectal cancer cell invasiveness. Additionally, in the presence of IL6, the cancer cells were able to secrete circulating microRNAs (miRs) miR-21 and miR-29b to further induce immune cell IL6 production. Activated immune cells were also found to release miR-21 into the tumor microenvironment. Taken together, these mechanistic findings provide a better understanding of intercellular communication between immune and cancer cells in the TME and offer insight into some of the key players that mediate this crosstalk. IMPLICATIONS: This study demonstrates that co-cultured cancer and immune cells communicate via IL6 and circulating miRs to sustain chronic inflammation and promote pro-metastatic cancer cell behavior. In addition, critical players are identified that mediate intercellular communication in the TME and suggest possible therapeutic approaches that target the microenvironment.