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 approximately 14%, despite advancements in treatment. SPP1+ tumor-associated macrophages (TAMs) are implicated in promoting tumor growth, angiogenesis, and immune evasion. Osteopontin (OPN), encoded by the SPP1 gene, is a critical regulator of TAMs M2 polarization and CRC metastasis. However, the mechanisms by which CRC-derived OPN interacts with M2-TAMs to promote metastasis remain unclear. Here, We found that OPN is highly expressed in metastatic CRC and is associated with poor prognosis. However, knockdown or overexpression of OPN in CRC cells did not directly affect tumor cell invasion and metastasis, which is inconsistent with previously reported trends. Additionally, OPN expression levels were positively correlated with M2-like TAMs infiltration. Using an in vitro co-culture system, we found that CRC-derived OPN induces M2-like polarization of TAMs, and the two mutually promote chemotactic migration. 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 recruitment of M2-TAMs and CRC tumor metastasis.Our study demonstrates that the OPN/CSF1/CSF1R/PI3K/AKT axis plays a crucial role in CRC metastasis. Blocking CSF1/CSF1R reduces M2-TAM infiltration and tumor metastasis, thereby enhancing the therapeutic efficacy for metastatic CRC.