Tumor-associated macrophage-specific LRRFIP1 promotes M2 macrophage polarization and progression of colorectal cancer via activation of the PI3K pathway.

BACKGROUND: Colorectal cancer (CRC) liver metastasis is a major factor affecting the prognosis of advanced CRC. Tumor-associated macrophages (TAMs), play a crucial role in CRC progression and metastasis by influencing the EMT of tumor cells. LRR binding FLII interacting protein 1, an epigenetic regulatory gene, a cancer-associated gene in a comprehensive analysis of human genome sequences; however, its role in CRC TAMs has not been elucidated. METHODS: We explored the expression and mechanism of action of LRRFIP1 in TAMs by single-cell transcriptome database analysis, immunostaining, flow cytometry, Western blotting, real-time quantitative PCR, enzyme-linked immunosorbent assay, and Transwell assay. Tumor growth and liver metastasis were examined in vivo. RESULTS: After knock down LRRFIP1 in TAMs in vitro, M2 phenotype and related cytokine expression were suppressed, whereas the promotion of CRC cell growth, migration, and invasion was inhibited. Interfering with LRRFIP1 did not further inhibit the TAMs phenotype or CRC progression after application of PI3K inhibitors or TGF-β receptor inhibitors. CONCLUSIONS: LRRFIP1 induces M2-like macrophage polarization via the PI3K/AKT signaling pathway, contributing to colorectal cancer progression. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-026-07759-1.