RUNX1/SLAMF3 Axis Drives Immunosuppression to Contribute to Colorectal Cancer Liver Metastasis by Blocking Phagocytosis and Depleting C1QC+ Tumor‐Associated Macrophages

Abstract Colorectal cancer liver metastasis (CRLM) is a leading cause of death in colorectal cancer (CRC) patients and is characterized by an immunosuppressive tumor microenvironment (TME). This study employs mouse in vivo selection to isolate highly metastatic CRLM derivatives for profiling their transcriptomic, proteomic, and metabolomic alterations associated with CRLM. Notably, the expression of SLAMF3 is significantly upregulated in CRLM derivatives and its knockdown effectively suppresses CRLM in mice. RUNX1 transcriptionally upregulates SLAMF3 expression and combined targeting of the RUNX1/SLAMF3 axis synergistically suppresses liver metastasis in mice. In parallel, SLAMF3 suppresses macrophage‐mediated phagocytosis of CRC cells through the SHP‐1/2/mTORC1 pathway. Conversely, SLAMF3 knockdown promotes M1 polarization in liver metastases and activates the CCL signaling pathway between macrophages and CD8 + T cells. It also reduces the exhausted CD8 + T cells in liver metastases and the expression of inhibitory receptors PD‐1 and TIM‐3, thus alleviating the immunosuppressive TME. Clinically, activation of the RUNX1/SLAMF3 axis is closely associated with CRLM progression and correlates with a reduced proportion of clinically beneficial C1QC⁺ tumor‐associated macrophages (TAMs). Collectively, these findings identify the RUNX1/SLAMF3 axis as a key driver of immunosuppressive TME remodeling and CRLM progression, highlighting its potential as a promising therapeutic target for CRLM.