Tumor interferon signaling regulates a multigenic resistance program to immune checkpoint blockade (ICB). Prolonged interferon signaling orchestrates PDL1-dependent and PDL1-independent resistance to ICB and combinations like radiation plus anti-CTLA4. Persistent type II interferon signaling allows tumors to acquire STAT1-related epigenomic changes and augments expression of interferon-stimulated genes and ligands for multiple T cell inhibitory receptors. Both type I and II interferons maintain this resistance program. Genetically or pharmacologically crippling the program interferes with multiple inhibitory pathways and expands distinct T cell populations with improved function despite expressing markers of severe exhaustion. Consequently, tumors resistant to multi-agent ICB are rendered responsive to ICB monotherapy. Biomarkers for interferon-driven resistance associate with clinical progression after anti-PD1 therapy. Thus, the duration of tumor interferon signaling augments adaptive resistance and inhibition of the interferon response bypasses requirements for combinatorial ICB therapies. Prolonged interferon signaling in tumor cells increases resistance to immune checkpoint blockade, and inhibiting this response can bypass the need for combination of these agents with other therapies.Tumor interferon signaling regulates a multigenic resistance program to immune checkpoint blockade (ICB). Prolonged interferon signaling orchestrates PDL1-dependent and PDL1-independent resistance to ICB and combinations like radiation plus anti-CTLA4. Persistent type II interferon signaling allows tumors to acquire STAT1-related epigenomic changes and augments expression of interferon-stimulated genes and ligands for multiple T cell inhibitory receptors. Both type I and II interferons maintain this resistance program. Genetically or pharmacologically crippling the program interferes with multiple inhibitory pathways and expands distinct T cell populations with improved function despite expressing markers of severe exhaustion. Consequently, tumors resistant to multi-agent ICB are rendered responsive to ICB monotherapy. Biomarkers for interferon-driven resistance associate with clinical progression after anti-PD1 therapy. Thus, the duration of tumor interferon signaling augments adaptive resistance and inhibition of the interferon response bypasses requirements for combinatorial ICB therapies. Prolonged interferon signaling in tumor cells increases resistance to immune checkpoint blockade, and inhibiting this response can bypass the need for combination of these agents with other therapies.