The oncogenic ability of matriptase is manifested in a variety of cancer types, rendering matriptase an attractive target for cancer therapy.3, 4 Small molecules can be designed to inhibit matriptase proteolytic activity via direct binding to the catalytic sites or preventing its cleaving maturation.28, 42, 43, 44 However, we report here a distinct strategy for small molecule design to blocking matriptase activity via inducing matriptase/HAI‐1 complex. This evidence concerns the gene SPINT1 and cancer.