GALNT6 promotes bladder cancer malignancy and immune escape by epithelial-mesenchymal transition and CD8+T cells

Abstract

Bladder cancer (BC) ranks as the fourth cancer in males and the tenth most common cancer worldwide. Conventional treatment modalities, including surgery, radiation, chemotherapy, and immunotherapy, have limited efficacy in certain advanced instances. The involvement of GALNT6-mediated aberrant O-glycosylation modification in several malignancies and immune evasion is a subject of speculation. However, its significance in BC has not been investigated. Through the integration of bioinformatics analysis and laboratory experimentation, we have successfully clarified the role of this GALNT6 in BC. Our investigation revealed that GALNT6 has significant expression in BC, and its expression level correlates with advanced stage and high grade, leading to poor overall survival. Moreover, both in vitro and in vivo tests demonstrate a strong correlation between elevated levels of GALNT6 and tumor growth, migration, and invasion. Furthermore, there is a negative correlation between elevated GALNT6 levels, the extent of CD8⁺T cell infiltration in the tumor microenvironment, and the prognosis of patients. Functional tests have shown that the increased expression of GALNT6 could enhance the malignant characteristics of cancer cells by activating the epithelial-mesenchymal transition (EMT) pathway. Ultimately, a bioinformatics study demonstrated that GALNT6 has the ability to engage with immunosuppressive receptors located on the outer layer of immune cells via MUC1. In brief, this study examined the impact of GALNT6-mediated abnormal O-glycosylation on the occurrence and progression of bladder cancer and its influence on immune evasion. It also elucidated the molecular mechanism underlying the interaction between tumor cells and immune cells, as well as the bidirectional signaling involved. These findings offer a novel theoretical foundation rooted in glycobiology for the clinical application of immunotherapy in BC.