CXCL10/CXCR3 axis facilitates the M2 polarization of macrophages in colorectal cancer via activating RAF

Colorectal cancer (CRC) is a common malignant tumor with high incidence and mortality. Tumor-associated macrophages (TAMs) play a crucial role in CRC progression, with M2 polarization promoting CRC development. The present study explored the role of the CXCL10/CXCR3 axis in the M2 polarization of TAMs in CRC. Bioinformatics analysis of three gene expression omnibus (GEO) datasets identified differentially expressed genes, with CXCL10 selected as a target due to its upregulation in CRC and various cancers via the Cancer Genome Atlas (TCGA) database mining. Subsequent experiments demonstrated that CRC cells overexpressed CXCL10, which promoted M2 polarization of macrophages by activating the rapidly accelerated fibrosarcoma (RAF)/extracellular signal-regulated kinase (ERK) pathway. CXCL10-overexpressed CRC cells increased M2 macrophage markers like CD206 and arginase 1 (Arg1), reduced M1 markers CD86 and inducible nitric oxide synthase (iNOS), and enhanced interleukin-10 (IL-10) release while decreasing IL-6 and tumor necrosis factor-alpha (TNF-α). CXCL10-overexpressed CRC cells also inhibited macrophage phagocytic capacity and lysosomal enzyme activity, crucial for tumor immunotherapy. Furthermore, macrophages stimulated by CXCL10-overexpressed CRC cells facilitated CRC cell proliferation and invasion. Inhibitors of CXCR3 or RAF reversed these effects, confirming that CXCL10 promoted M2 polarization via the CXCR3/RAF/ERK pathway. Overall, the CXCL10/CXCR3 axis played a key role in CRC progression by inducing M2 polarization of macrophages via the RAF/ERK pathway, suggesting that CXCL10/CXCR3 axis may be a potential therapeutic target for CRC immunotherapy.