Metastatic colorectal cancer (mCRC) presents a significant health challenge, with poor patient outcomes and limited treatment options. Untreated mCRC carries a bleak prognosis, with a 5-year survival rate below 10% and a median survival of only 5 months. Metastatic spread to the liver, due to its anatomical proximity, and to the lungs is common in mCRC, often indicating advanced disease and impacting treatment strategies. This study aims to elucidate the temporal and spatial dynamics of cell populations and their protein expression through the metastatic process, utilizing both a murine metastasis model and human primary and metastatic tumor samples. We employed a multi-modal approach, combining CyTOF characterization of immune and stromal landscapes within murine tumors with in-depth proteomic analysis of isolated cell populations. Additionally, we investigated human tumor samples to gain insights into the proteomic landscape of CRC in the spatial dimension. Our findings reveal a complex interplay between different cell types in tumor progression, highlighting the tissue specific role played by the immune cells in shaping the tumor microenvironment. Late-stage tumors are dominated by immunosuppressive macrophages, monocytes, dendritic cells, and cancer-associated fibroblasts, while early-stage tumors mostly encounter tissue-specific immune surveyors. Proteomic analysis identified distinct protein expression profiles in liver, lung, and primary human colorectal cancer (hCRC). Liver metastases showed enrichment in pathways related to drug metabolism, fatty acid metabolism, amino acid biosynthesis, and ECM-receptor interaction/focal adhesion. Compared to primary and lung tumors, liver metastases had lower levels of cell cycle and nucleotide biosynthesis proteins, but higher levels of certain metabolic and innate immune proteins. These findings emphasize the importance of studying organ-specific protein expression patterns and cellular heterogeneity in guiding therapies for metastatic CRC.