Kras is essential to the immunosuppressive tumor microenvironment in colon cancer via regulation of pioneer transcription factors Colorectal cancer (CRC) is the second leading cause of cancer death in the United States and is particularly deadly if diagnosed at late stage. The vast majority of colon cancers are sporadic with a stereotypical pattern of accumulated mutations. The initiating event in sporadic colon cancer is a loss-of-function mutation in adenomatous-polyposis coli (APC), followed by the mutation of p53 and an activating mutation in the oncogene KRAS. KRAS is one of the most frequently mutated oncogenes in cancer and is a predictive biomarker of therapeutic response. In order to investigate how mutational burden in colon cancer regulates the immune microenvironment and cancer metabolism, three separate murine models were assessed using a multi-omics approach. We have established a mouse model of colon carcinogenesis with i) Apcloss, ii) expression of mutant KrasG12D, iii) homozygotic deletion of p53 iv) using a tamoxifen-inducible Cre line that is only expressed in the colon epithelial cells (Cdx2ER-Cre). We refer to these mice as the TripleMutmice. We also utilized the Apc deletion mouse model, denoted SingleMut, and an Apc and a p53 homozygous deletion, denoted DoubleMut. Kras mutation in the TripleMutresults in a more aggressive and invasive phenotype, higher colon tumor burden, and metastasis to the liver and the lung. Consistent with the enhanced tumor progression, increased mutational burden leads to decrease survival. In addition, the TripleMutmice are resistant to anti-IL17 or PD-L1 neutralizing antibody whereas SingleMutand DoubleMutmice are responsive to both immune based therapies. I employed a multi-omics approach with mass cytometry (CyToF) and RNA-SEQ to understand how KRAS mutation alters the immune infiltrate. CyToF is a high-throughput flow-based technique using simultaneous metal labeling of up to 50 antibody markers (21). The TripleMutmice have a decrease in anti-tumor inflammatory pathways and infiltration of activated T-cells compared to the DoubleMutmice. This data suggests KRAS mutation modulates an immunosuppressive microenvironment. Network analysis of the RNA-SEQ data shows that the genes differentially expressed between the DoubleMutand TripleMutprimarily belong to three families: the Polycomb Repressor Complex 2 (PRC2), STAT/IRF signaling, Wnt/beta-catenin signaling, and HNF4A. We found that human colon cancer cell lines are highly sensitive to PRC2 inhibitors, and plan to use chemical and genetic approaches to inhibit all three of these main pathways in the TripleMutmice as a potentially combinatorial therapy.