Mechanistically, we elucidate that the GPR137-medicated GC cell malignancy is through its regulation of Hippo signaling, particularly by its binding to MST kinases, which dampens the MST-LATS protein–protein complex formation and subsequently triggers the transactivation of YAP/TAZ-mediated downstream target genes, consequently resulting in the enhanced cancer cell malignancy. Here, GPR137 is linked to cancer.