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Background Colorectal cancer (CRC) remains the third most common cancer and the second leading cause of cancer-related deaths worldwide. T cell infiltration in tumors is strongly associated with improved disease outcomes, irrespective of microsatellite instability status. However, microsatellite stable (MSS) CRC—which accounts for over 90% of metastatic CRC cases responds poorly to current T cell-targeting immune checkpoint blockade (ICB) therapies. Liver metastasis, present in up to 70% of patients with metastatic CRC, is associated with worse prognosis and immunotherapy resistance. The failure of PD-1-targeted therapies in metastatic CRC underscores the presence of dominant, alternative immunosuppressive mechanisms inhibiting effector T cell function in this context. Key drivers of these alternative mechanisms are myeloid cells, particularly monocyte-macrophages (mo-macs), which play a pivotal role in modulating anti-tumor immune responses.Methods We combined scRNA-seq of human and mouse CRC with genetic and pharmacological functional studies to define the contribution of immunosuppressive mo-macs to tumor progression and immunotherapy resistance in primary and metastatic CRC.Results Deep molecular profiling of human and mouse CRC revealed that mo-macs dominate CRC lesions and liver metastases and adopt highly suppressive phenotypes. To understand the local tumor cues that drive immunosuppressive programs in tumor-infiltrating mo-macs we carried out single-cell RNA-seq of PBMCs, normal-adjacent tissue and primary tumor lesions from 30 treatment naïve MSS CRC patients and in immunotherapy-refractory orthotopic primary and metastatic mouse MSS CRC tumor lesions. In both human and mouse, we saw a striking upregulation of IL4 signalling in monocytes upon entry into tumor lesions and differentiation into mo-macs. Reporter mice revealed local IL-4 secretion was markedly elevated in primary and metastatic lesions, primarily by tumor-infiltrating eosinophils, which was driven by interactions with IL-33 secreting cancer-associated fibroblasts within the TME.Using genetic and pharmacological approaches we demonstrated that this pathogenic stromal-myeloid axis represents a major driver of tumor progression and immunotherapy resistance in metastatic MSS CRC. Deletion of the IL4-Ra receptor specifically in mo-macs or treatment with an IL4-Ra blocking antibody reversed immunosuppression within the TME, expanded cytotoxic CD8+ T cells and sensitized both primary and metastatic tumors to ICB.Conclusions We have identified a major stromal-myeloid axis in MSS metastatic colorectal cancer which acts locally to sustain mo-mac driven immunosuppressive programs, contributing to tumor progression and immunotherapy resistance. Disruption of this axis presents a unique opportunity to overcome resistance to current ICB treatment and has the potential to transform outcomes for MSS CRC patients.