Colorectal cancer-derived osteopontin rewires macrophages into a pro-metastatic M2 state via the PI3K/AKT/CSF1-CSF1R axis.

Metastasis remains the primary cause of mortality in colorectal cancer (CRC), with a 5-year survival rate of ~14%, despite therapeutic advances. SPP1+ tumor-associated macrophages (TAMs) are implicated in promoting tumor progression, angiogenesis, and immune evasion. Osteopontin (OPN), encoded by the SPP1 gene, is a critical regulator of TAMs M2 polarization and CRC metastasis when derived from TAMs. However, it remains unclear whether CRC-derived OPN interacts with M2-like TAMs to promote metastasis and what the underlying mechanisms are. Here, we found that OPN is highly expressed in metastatic CRC and is associated with poor prognosis. Contrary to prior reports, neither knockdown nor overexpression of OPN in CRC cells directly altered tumor cell invasion and migration. Rather, OPN expression levels were positively correlated with M2-like TAMs infiltration. The co-culture system revealed bidirectional chemotactic interactions between CRC cells-derived OPN and M2-like TAMs. Mechanistically, high OPN expression activates the PI3K/AKT signaling pathway in macrophages, promoting the secretion of CSF1, which induces M2-like polarization of macrophages to facilitate tumor metastasis. Finally, in a mouse metastasis model, blocking the CSF1/CSF1R axis with a CSF1R inhibitor reduced the M2-like TAMs recruitment and CRC tumor metastasis burden. Our study demonstrates that the OPN/PI3K/AKT/CSF1-CSF1R axis plays a crucial role in CRC metastasis. Blocking the CSF1/CSF1R axis reduces M2-like TAMs infiltration and tumor metastasis, offering a promising strategy for metastatic CRC.