AMIGO2 (adhesion molecule with Ig like domain 2) functions as a transmembrane adhesion molecule and signaling scaffold with critical roles in cancer metastasis and cell survival. AMIGO2 promotes cancer cell adhesion to hepatic endothelial cells, serving as a driver of liver metastasis in gastric, colorectal, and pancreatic cancers 1 2 3. The protein can be released in extracellular vesicles, enhancing endothelial cell adhesion to cancer cells and facilitating metastatic colonization 4. AMIGO2 functions as a membrane anchor for PDK1, controlling cell survival and angiogenesis through Akt pathway activation 5. In colorectal cancer, nuclear translocation of AMIGO2 induces epithelial-mesenchymal transition (EMT) by activating TGFβ/Smad signaling, enhancing invasive potential 6. Additionally, AMIGO2 confers chemoresistance by suppressing GSDME-mediated pyroptosis in non-small cell lung cancer through PDK1/Akt signaling 7, and promotes bladder cancer proliferation and migration via PPAR-γ regulation 8. AMIGO2 expression correlates with poor prognosis and serves as an independent prognostic factor in multiple cancer types, making it an attractive therapeutic target for metastasis prevention and overcoming drug resistance.