TIPE regulates TGFB2 expression and induces extracellular M2 polarization in CRC.

The immunosuppressive tumor microenvironment (TME) is a critical determinant of therapeutic resistance in colorectal cancer (CRC). The TME encompasses diverse cellular and stromal elements, including tumor cells, immune cells, extracellular matrix, and lymphatic vessels. Among these components, tumor-associated macrophages predominate both quantitatively and functionally, with M2-polarized macrophages being the principal subset responsible for immunosuppression. Identifying genes that promote M2 polarization from CRC would provide a more targeted approach to addressing this issue at its root. In this study, we demonstrate that TIPE derived from CRC indirectly stimulates extracellular M2 polarization. Mechanistically, TIPE activates the P38 MAPK signaling pathway, leading to increased expression and secretion of TGFB2, which subsequently acts on extracellular macrophages to induce M2 polarization. Moreover, M2 macrophages polarized by CRC-derived factors exert a feedback loop that enhances CRC proliferation, migration, and invasion, with the effect intensifying as TIPE expression in CRC increases. Animal experiments have also revealed that TGFB2 induced by TIPE can disseminate systemically via the bloodstream, influencing not only peritumoral macrophages but also inducing M2 polarization in macrophages in distant organs. Collectively, our findings indicate that TIPE from CRC can indirectly polarize extracellular macrophages to an M2 phenotype, thereby amplifying the malignant behavior of CRC.