This study shows that circulating tumor cells, before dissemination from a primary tumor, are empowered to escape NK cell surveillance and form metastasis by cross‐talking with mesenchymal stromal cells in the tumor microenvironment via an intercellular cGAS‐cGAMP‐STING‐IFNβ‐HLA‐I signaling loop. Here, IFNB1 is linked to neoplasm.