The effect and mechanism of TIPE in promoting M2 polarization through DcR3 in the microenvironment of colorectal cancer

Elevated expression of tumor necrosis factor α-induced protein 8 (TIPE) is observed in colorectal cancer (CRC) and is known to regulate decoy receptor 3 (DcR3) expression while promoting M2 polarization of macrophages. However, the precise role of DcR3 in macrophage M2 polarization remains to be elucidated. We employed bioinformatic analysis alongside in vitro and in vivo experimental approaches to investigate the regulatory mechanism by which TIPE influences macrophage M2 polarization in CRC. TIPE expression in CRC tissues positively correlates with M2 macrophage markers (CD206, CD163, IL-10). Functionally, TIPE promotes M2 polarization of macrophages by upregulating DcR3. Mechanistically, DcR3 binds to heparan sulfate proteoglycan 2 (HSPG2) in a heparan sulfate (HS)-dependent manner, leading to activation of the protein kinase Bα1 (AKT1) signaling pathway. AKT1 activation not only directly drives M2 polarization but also enhances macrophage chemotaxis and recruitment toward CRC cells by upregulating the chemokine CXCL8. This study reveals a novel mechanism through which TIPE regulates M2 macrophage polarization and function via DcR3, offering new perspectives for the diagnosis and therapeutic targeting of CRC.