Role of Stabilin-1 Expressing Macrophages in Colorectal Liver Metastasis

Colorectal cancer (CRC) is the 2nd most common cause of cancer-related mortality, primarily due to its spread to distant organs. Colorectal liver metastasis (CRLM) is the foremost form of CRC spread due to the anatomical link between the liver and intestine. Despite advancements in diagnostic tools and adjuvant therapies, the survival rate of CRLM remains low, indicating the significant need to identify targetable mechanisms. Stabilin-1 (STAB1), a scavenger receptor expressed on tumor-associated macrophages, has been linked to tumorigenesis and poor outcomes in various cancers. However, the role of STAB1 in CRLM is not known. Here, we investigated the role of STAB1 expression in a preclinical model of CRLM. Wild-type (WT) and Stab1 knockout (KO) mice were intrasplenically injected with saline (vehicle control) or MC38 CRC cells, followed by assessment of tumor burden, liver injury, immune profiles, and macrophage phenotypic markers. As expected, CRLM burden and metastasis-promoting cytokines and macrophages were significantly enhanced in WT mice injected with MC38 cells compared to vehicle controls. In contrast, Stab1 KO mice showed a blunted expression of prometastatic factors, indicating potential protection from CRLM. However, the tumor burden was not consistently reduced in Stab1 KO mice, with differences between the sexes observed. Notably,male Stab1 KO mice displayed reduced CRLM while female Stab1 KO mice exhibited increased CRLM with an accompanying 2-fold accumulation of tumor-promoting M2-type macrophages at the liver-tumor interface. These findings suggest a sex-dependent role of STAB1 in CRLM development and highlight its potential as a therapeutic target.