Type I interferons (IFNs), which activate many IFN-stimulated genes (ISGs), are known to regulate tumorigenesis. However, little is known regarding how various ISGs coordinate with one another in developing anti-tumor effects. Here we report that the ISG, UBA7, is a tumor suppressor in breast cancer. UBA7 encodes an enzyme that catalyzes the covalent conjugation of the ubiquitin-like protein product of another ISG (ISG15) to cellular proteins in a process known as “ISGylation”. ISGylation of other ISGs, including STAT1 and STAT2, synergistically facilitates production of chemokine-receptor ligands to attract cytotoxic T cells. These gene activation events are further linked to clustering and nuclear relocalization of STAT1/2 within IFN-induced PML bodies. Importantly, this coordinated ISG-ISGylation network plays a central role in suppressing murine breast cancer growth and metastasis, which parallels improved survival in breast cancer patients. These findings reveal a cooperative IFN-inducible gene network in orchestrating a tumor suppressive microenvironment. Copyright 2020, American Association for Cancer Research.