CXCL9 is a chemokine critical for immune cell trafficking to the tumour site and its expression is a strong predictors of response to immune checkpoint blockade therapy. Strategies designed to enhance the expression of CXCL9 are therefore highly desirable. By integrating GFP directly downstream of the final exon of CXCL9 using CRISPR-mediated knock-in, we developed a novel reporter cell line that enabled whole-genome CRISPR screening for regulators of CXCL9. IRF1 was identified as a potent negative regulator of CXCL9, a finding that was validated in several tumour lines and primary immune cells from both mice and humans. The negative regulation of CXCL9 by IRF1 was attributable to the induction of SOCS1 expression by IRF1. Subsequently, IRF1 and SOCS1 were validated as viable therapeutic targets as their knockout from tumour cells or the haematopoietic compartment led to enhanced therapeutic responses to CAR T cells or immune checkpoint inhibitors.