Migration and invasion inhibitory protein inhibits M2 macrophage polarization to suppress colorectal cancer progression through the STING–NFκB2–IL10 axis

Objectives: This study aimed to determine the role and mechanism underlying migration and invasion inhibitory protein (MIIP) modulation in M2 macrophages within the tumor microenvironment and the potential of targeting the MIIP– stimulator of interferon genes (STING) pathway in colorectal cancer (CRC) therapy. Methods: MIIP expression was analyzed for associations with the STING pathway and M2 macrophage infiltration using public datasets and clinical CRC samples. CRC cells were genetically modified using lentiviral vectors to overexpress or silence MIIP and STING. The interactions of genetically modified CRC cells with macrophages were studied in co-culture systems. Techniques, including immunofluorescence staining, RT-qPCR, western blot, ELISA, flow cytometry, and Transwell migration and invasion assays, were used to evaluate the crosstalk between CRC cells and macrophages. An orthotopic mouse CRC model was developed to study the effects of MIIP on M2 macrophage polarization and tumor metastasis through the STING–NFκB2–IL10 axis. The therapeutic significance of a STING antagonist was also assessed in vivo. Results: Analyses of The Cancer Genome Atlas (TCGA) cohort and our CRC cohort revealed low MIIP expression is associated with STING pathway activation, increased M2 macrophage infiltration, and poor clinical outcomes. The results of functional experiments demonstrated that MIIP inhibits IL10 production via the STING–TRAF3–NFκB2 axis in CRC cells, suppressing M2 macrophage polarization in co-culture systems. Conversely, M2 macrophages promoted CRC cell migration and invasion in an IL10-dependent manner. In vitro and in vivo studies confirmed that the MIIP-mediated feedback loop between CRC cells and macrophages depends on the STING–NFκB2–IL10 axis. Furthermore, inhibition of STING expression in a mouse model reduced M2 macrophage polarization and tumor metastasis. Conclusions: This study established MIIP as a crucial regulator of macrophage polarization in the CRC tumor microenvironment, providing new insights into the role in suppressing CRC progression and immune–tumor crosstalk. These findings highlight the potential of targeting the STING pathway as a therapeutic strategy for CRC patients who respond poorly to immune checkpoint inhibitors.