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Tumor-associated macrophages (TAMs), especially SPP1⁺TAMs are associated with poor prognosis of colorectal cancer (CRC). However, the underlying mechanism remains unclear, and the therapeutic targets have yet to be identified.

Single-cell RNA sequencing (scRNA-seq) data were used to explore the interactions between SPP1⁺TAMs and CRC cells. TAM co-culture model, liver metastasis models and clinical tissue microarray (n=42) were used to validate the key secreted cellular factor and its associated receptor that mediated the interactions between SPP1⁺TAMs and CRC cells.

We found that migration inhibitory factor (MIF) was the most important signaling molecule involved in the interaction between SPP1⁺TAMs and CRC cells, as revealed by cellular interaction analysis of integrated scRNA-seq datasets. Interestingly, SPP1 was co-expressed with MIF receptor CD44 on SPP1⁺TAMs. When SPP1⁺TAMs was activated, CD44 was crucial for MIF-mediated angiogenesis. Our data showed that CRC cells activated SPP1⁺TAMs, which was abolished by blocking the MIF signaling both in vitro and in vivo. Furthermore, the pathological role of MIF is suggested by the elevated expression of MIF and activation of SPP1⁺TAMs in CRC patients, as demonstrated in clinical tissue microarray. Further mechanistic studies revealed that POU2F2 was a crucial transcription factor mediating MIF-driven activation of SPP1⁺TAMs, and that BCL9L was a direct downstream target of POU2F2.

Our findings suggest that the MIF/CD44/POU2F2/BCL9L signaling axis is involved in the proangiogenic capacity of activated SPP1⁺TAMs, thereby enhances CRC metastasis. Targeting this novel signaling axis can effectively suppress the SPP1⁺TAM activation, which represents a promising and pivotal strategy for managing CRC metastasis.