GALNT6 dual regulates innate immunity STING signaling and PD-L1 expression to promote immune evasion in pancreatic ductal adenocarcinoma

Abstract

Despite significant advancements in immunotherapy for cancer treatment, its effectiveness in pancreatic ductal adenocarcinoma (PDAC) remains disappointing, which is greatly due to the unique immunosuppressive microenvironment of PDAC. Here, we focus on the involvement of GALNT6 in immune evasion mechanisms in PDAC. Our results reveal a negative relationship between GALNT6 expression and immune cell infiltration in PDAC. Knockdown of GALNT6 enhances PDAC cells sensitivity to cytotoxic T cells and macrophages. Mechanistically, GALNT6-mediated glycosylation blocks the translocation of STING (stimulator of interferon genes) and accelerates its degradation in a cGAS-independent manner, leading to reduced levels of type I interferon (IFN-β) and CCL5 and CXCL10, thus promoting PDAC immune evasion by inhibiting cytotoxic CD8⁺ T cell and macrophage infiltration. Furthermore, GALNT6 stabilizes PD-L1 by blocking its ubiquitin-proteasome degradation, thereby promoting tumor immune evasion. Notably, the combination of an O-glycosylation inhibitor with PD-1/PD-L1 inhibitors synergistically enhances the anti-cancer immune response. In summary, these findings highlight GALNT6 as a critical player in immune evasion, and targeting GALNT6 could serve as a valuable approach to boost anti-tumor immunity in PDAC patients.