Despite advances in the treatment of metastatic colorectal cancer (mCRC), 5-year survival is only 14%. Cancer immunotherapy has provided significant clinical benefit but the use of currently available checkpoint inhibitors is limited to only 5% of mCRC patients. 95% of mCRC patients who have a pMMR/MSI-L phenotype show low or no T cell infiltration but are frequently infiltrated by myeloid cells, which drive immunosuppression and therapy resistance. Here we propose to identify and validate new immunomodulatory approaches for high-risk (HR) pMMR/MSI-L stage IV mCRC patients by reprogramming tumor-infiltrating myeloid cells using epigenetic modifiers and myeloid-specific checkpoint inhibitors. We propose to (1) define immunosuppressive myeloid cell landscapes for HR mCRC patient stratification using single-cell multi-omics profiling, (2) identify and validate epigenetic modifiers that reprogram immunosuppressive myeloid cells using a CRISPR screen with single cell phenotypic read-out, (3) generate patient-derived CRC xenografts and reconstruct the tumor-immune microenvironment in a novel MISTRG+ humanized mouse model, and (4) validate different myeloid-reprogramming therapies and combination strategies in CRC-PDX humanized MISTRG+ mice using a multi-omics approach defining the responsive subgroup. Altogether this strategy will provide clinicians with a framework for precision diagnostics and myeloid therapy including effective combination strategies for HR mCRC patients.