<p>Indoleamine-2,3-dioxygenase (IDO) and arginase1 (ARG1) are immunosuppressive enzymes frequently overexpressed in cancer, with higher expression in colorectal cancer primary tumours paradoxically linked to favourable survival. Their significance in metastases remains unexplored. Employing multiplexed immunohistochemistry and supervised machine learning-based digital image analysis, we analysed the IDO and ARG1 expression in monocytic cells, granulocytes, mast-cells and tumour cells in 91 resected pulmonary metastases from 53 corresponding primary tumours. We also evaluated the spatial distribution of IDO⁺ and ARG1⁺ cells relative to tumour cells and compared these patterns between metastases and primary tumours. In metastases, higher IDO⁺ monocytic cell densities in the tumour centre were associated with favourable survival (adjusted HR 0.17, 95%CI 0.05–0.59, <i>p</i> = 0.005), while higher IDO^– monocytic cell densities in the invasive margins were associated with worse survival (adjusted HR 4.19, 95%CI 1.45–12.05, <i>p</i> = 0.008). Moreover, higher densities of IDO⁺HLA-DR⁻ immature monocytic cells and IDO⁺FCGR3⁺ monocytic cells in the invasive margin were also associated with poor survival, after adjusting for T-cell densities (adjusted HRs 26.4, 95%CI 4.95 − 140.42, <i>p</i> &lt; 0.001 and 3.91 95%CI 0.97 − 15.76, <i>p</i> = 0.056, respectively). These findings provide detailed insights into the immunosuppressive myeloid cell landscape in colorectal cancer pulmonary metastases, highlighting key differences from primary tumours and potential implications for therapy development.</p>