Glioblastoma (GB) is the most common and aggressive form of malignant primary brain tumors in adults. Immunotherapeutics are a promising avenue of treatment, but their effectiveness can improve if we further understand the immune system's role in tumor progression. The tumor extracellular matrix (ECM) and tumor-associated macrophages promote tumor growth and invasion, but the effect of the tumor ECM on macrophage activity is unknown. We hypothesize that the physical and biological properties of the tumor ECM drive macrophage phenotypes that promote tumor growth. In this study, we investigated the ECM-macrophage interface from both a biological and physical perspective. We found that tumor ECM stiffness and composition promoted the proinflammatory activity of macrophages in short-term cultures. This is surprising considering most investigators have found that macrophages have anti-inflammatory activity in mouse tumors. We also examined whether proinflammatory mediators were present in GB tumors. We found that TNF-alpha, a proinflammatory cytokine, was present in 7 out of 7 tumors of patients with GB. Also, we found that IL-10, an anti-inflammatory cytokine, was present in 6 out of 6 tumors of patients with GB. Our results show a need to clinically define the inflammatory activity in the tumor microenvironment and identify the mechanisms that drive inflammation.