SRP330319 PRJNA750249 GSE180942 Cancer Cell Resistance to IFN? Can Occur via Enhanced Double-Strand Break Repair Pathway Activity [CRISPR screen] The pleiotropic cytokine interferon-gamma (IFN?) is known to be associated with cytostatic, anti-proliferation, and pro-apoptosis functions in cancer cells. However, cancer cells can become resistant to IFN?, and the underlying mechanism is not fully understood. To investigate the potential IFN? resistant mechanisms, we performed IFN? sensitivity screens in more than 40 cancer cell lines and characterized the sensitive and resistant cell lines. By applying CRISPR screening and transcriptomic profiling in both IFN? sensitive and resistant cells, we discovered that activation of double-strand break (DSB) repair genes could result in IFN? resistance in cancer cells. In addition, suppression of single-strand break (SSB) repair genes increased the essentiality of DSB repair genes after IFN? treatment. The relationship between the activation of DSB repair genes and IFN? resistance was further confirmed in clinical tumor profiles from The Cancer Genome Atlas (TCGA) and immune checkpoint blockade (ICB) cohorts. Our study provides a comprehensive resource to elucidate IFN? resistance in cancer and has the potential to inform combinational therapeutic strategies to overcome immunotherapy resistance. Overall design: To further validate the molecular mechanisms related to IFN? resistance, we performed CRISPR knockout (KO) screens on four IFN? resistant cell lines (MCF7, 786O, HCT116, HUH6) and five sensitive cell lines (A549, NCIH1437, MDAMB231, PC9, CALU1). GSE180942 pubmed 36629846 parent_bioproject PRJNA750105