Distinct and cooperative roles of host and tumor Osteopontin in colorectal cancer liver metastasis

Summary Osteopontin (OPN) is a secreted phosphoprotein implicated in colorectal cancer liver metastasis (CRCLM), yet the distinct spatial contributions of host-and tumor-derived OPN in driving this disease remain unclear. Using a 2 x 2 genetic knockout mouse model targeting OPN in host and tumor compartments, combined with spatial transcriptomics, we investigated compartment-specific OPN functions in CRCLM. Tumor-derived OPN promotes tumor proliferation through MEK/ERK signaling. Host OPN licenses monocyte-to-macrophage differentiation, while tumor OPN polarizes macrophages towards an M2-like state. Both host and tumor OPN suppress T cells in the tumor microenvironment, whereas loss of host OPN reveals an interferon-driven, anti-tumor niche. Translational studies using OPN-blockade immunotherapy in syngeneic and patient-derived xenograft mouse models reduced tumor burden and enhanced T cell infiltration. Together, these findings redefine the OPN-myeloid paradigm in CRC and nominate OPN as a potential therapeutic target. Competing Interest Statement The authors have declared no competing interest.