Tumor microenvironment in cancer is influenced by the interaction of the cell with physicochemical and mechanical signals of the extracellular matrix (ECM). It has been reported the development and metastasis of cancer are regulated by mechanical stimuli, and changes in mechanotransduction signaling by bio-mechanical cues are closely related to cancer malignancy. In particular, physicochemical characteristics of ECM in gastric cancer (GC) significantly altered, however, there is no study on the mechanotransduction. Therefore, we developed a new cancer therapeutic approach by analyzing ECM-specific mechanotransduction mechanism and GC malignancy. For this study, 1) we established a physiologically-relevant 3-dimensional (3D) culture model by analyzing ECM characteristics of GC tissues, 2) analyzed mechanotransduction signaling of GC cells according to the physical characteristics of ECM, and 3) finally developed a new cancer therapy strategy by targeting mechanotransduction.