骨桥蛋白在空间上重塑肿瘤-免疫生态位以促进结肠癌肝转移

Osteopontin (OPN) is a secreted extracellular matrix protein that regulates T cells, myeloid cells, and tumor cells. Although OPN is a known biomarker of colorectal cancer (CRC) progression and liver metastasis, the cellular circuitry linking OPN-producing and OPN-responsive cells in the metastatic liver microenvironment remains poorly defined. Here, we investigated how tumor-derived and host-derived OPN remodel this microenvironment to promote disease progression. Using orthotopic mouse models, we found that deleting OPN in either tumor cells or host cells was sufficient to increase T cell infiltration and suppress liver metastasis, whereas dual deletion produced an even greater reduction in metastatic burden. To define niche-specific programs, we applied COSMX spatial transcriptomics to mouse liver metastasis tissues, profiling 1,000 signature genes across 1,179,351 cells. We determined that tumor-derived OPN reprograms immune-inactive niches enriched for highly proliferative cancer cells, and that host-derived OPN rewires niches characterized by low monocyte and T cell abundance and enriched stem-like cancer cells. Mechanistically, tumor-derived OPN activates the MEK/ERK pathway to promote tumor cell proliferation. To translate these findings, we tested OPN blockade immunotherapy in mouse models. OPN blockade immunotherapy significantly suppressed tumor growth and increased immune cell infiltration in both syngeneic models and humanized mouse models of CRC liver metastasis. Together, these data identify tumor- and host-derived OPN as nonredundant, pro-metastatic drivers of proliferation, immune suppression, and niche remodeling, and support OPN inhibition as a promising immunomodulatory strategy for CRC liver metastasis.