METTL3-driven m6A modification promotes tumor progression and immune evasion in hypoxic pancreatic cancer by enhancing ADAM10-mediated MICA shedding

Pancreatic cancer is characterized by asymptomatic early stages, fast progression, and dismal survival rates. Therefore, a better understanding of immune evasion is required to create more effective treatments. m6A methylation is linked to pancreatic cancer, particularly in hypoxia-induced immune escape. GEO microarray datasets identified pancreatic cancer differentially expressed genes (DEGs) and m6A modification regulators. Compared with controls, pancreatic cancer samples showed increased METTL3 levels. METTL3 levels are strongly associated with HIF1A, a key component of the hypoxic tumor microenvironment, suggesting its involvement in tumor development and immune evasion. HIF1A expression levels divided pancreatic tumor tissues into high- and low-HIF1A groups. The high-HIF1A group showed higher METTL3 and MICA levels. Further histopathological, immunohistochemical, and m6A modification studies indicated that METTL3 expression and m6A modification increased, especially under hypoxic conditions. In normoxic pancreatic cancer cell lines, METTL3 overexpression boosted cell survival, migration, reduced apoptosis, and facilitated immune evasion by lowering MICA-positive cells and increasing sMICA, decreasing NKG2D-positive NK92 cells, and impairing NK92 cell death. Hypoxic METTL3 knockdown reduced cell survival and migration, enhanced apoptosis, increased MICA-positive cells and decreased sMICA levels, and boosted NKG2D-positive NK92 cells and pancreatic cancer cell death, suggesting reduction of immune evasion. Moreover, the in vivo xenograft model further confirmed that METTL3 knockdown reduced tumor growth and increased NK cell infiltration. METTL3 stabilizes ADAM10 mRNA through m6A modification. Under hypoxic conditions, ADAM10 overexpression had effects opposite to those of METTL3 knockdown in pancreatic cancer cells and NK92 cells. It partially abolished METTL3’s effects, suggesting that m6A modification might mediate METTL3’s effects on hypoxia-related pancreatic cancer immune evasion. In conclusion, targeting METTL3 or ADAM10, or intervention in the m6A modification pathway, may provide novel therapeutic avenues, particularly for pancreatic cancer cells’ immune-evasive tactics.