In this study, we use CRISPR-Cas9 screening to identify mediators of sensitivity and resistance to IFN-γ in colorectal adenocarcinoma (CRC), and use cytidine base editors (CBEs) and adenine base editors (ABEs) to perform mutagenesis of the top-scoring genes, thereby systematically mapping loss-of-function (LOF) and gain-of-function (GOF) variants modulating IFN-γ pathway activity (Figure 1A), including VUS associated with diseases such as cancer. Here, IFNG is linked to cancer.