The study investigates the role of interferon (IFN) signaling in tumor resistance to immune checkpoint blockade (ICB) therapy. Prolonged IFN signaling, particularly type II interferon (IFNG), is shown to orchestrate both PDL1-dependent and PDL1-independent resistance to ICB, including combinations like radiation plus anti-CTLA4. This resistance is driven by STAT1-related epigenomic changes and increased expression of interferon-stimulated genes (ISGs) and ligands for multiple T cell inhibitory receptors (TCIRs). Both type I and II IFNs contribute to maintaining this resistance program. Genetic or pharmacological interference with IFN signaling can disrupt multiple inhibitory pathways, expand distinct T cell populations with improved function, and render tumors responsive to ICB monotherapy. Additionally, biomarkers for interferon-driven resistance, such as ISGs, are associated with clinical progression after anti-PD1 therapy. The findings highlight the importance of targeting IFN-driven resistance to enhance the efficacy of ICB therapies.The study investigates the role of interferon (IFN) signaling in tumor resistance to immune checkpoint blockade (ICB) therapy. Prolonged IFN signaling, particularly type II interferon (IFNG), is shown to orchestrate both PDL1-dependent and PDL1-independent resistance to ICB, including combinations like radiation plus anti-CTLA4. This resistance is driven by STAT1-related epigenomic changes and increased expression of interferon-stimulated genes (ISGs) and ligands for multiple T cell inhibitory receptors (TCIRs). Both type I and II IFNs contribute to maintaining this resistance program. Genetic or pharmacological interference with IFN signaling can disrupt multiple inhibitory pathways, expand distinct T cell populations with improved function, and render tumors responsive to ICB monotherapy. Additionally, biomarkers for interferon-driven resistance, such as ISGs, are associated with clinical progression after anti-PD1 therapy. The findings highlight the importance of targeting IFN-driven resistance to enhance the efficacy of ICB therapies.