There is a complex interplay existing between the tumor microenvironment and cellular function, while the influence of tumor biophysical signals on the macrophage function remain unclear. Herein, we constructed a three dimensional hydrogel model to study the symphysial effect of physical signal (stiffness) and biological signal (tumor cells) on macrophage polarization in different stage of tumor progression. In the absence of biological signal, the macrophage response was slightly changed with different stiffness (100 Pa, 300 Pa, and 900 Pa). Once co-incubated with the tumor cell, macrophage induced more significant cancer facilitated cytokines (e.g. IL-10, MMP-9) and chemokines (MCP-1). In contrast to the education role from the co-cultured cancer cells, a stiffness around the normal tissue (100 Pa, CO-L group) provided a physical cue for cancer cell regression. This cue triggered the active role of M1 type macrophages (e.g. IL-12), indicating the interacting role of stiffness in the presence of cancer cell. The stiffness around the premalignant tissue (M, 300 Pa) induced much higher level of cytokines (e.g. IL-6, IL-10, IL-12, CD86, and CD206), while the immune activation cytokines (M1 type) was largely attenuated at high stiffness (900 Pa). This study revealed the pleiotropic tuning of macrophage function under different biophysical signals, which provided important knowledge for cancer progress and may benefit the design of cancer-related therapies.