QDPR deficiency drives immune suppression in pancreatic cancer.

The relevance of biopterin metabolism in resistance to immune checkpoint blockade (ICB) therapy remains unknown. We demonstrate that the deficiency of quinoid dihydropteridine reductase (QDPR), a critical enzyme regulating biopterin metabolism, causes metabolite dihydrobiopterin (BH2) accumulation and decreases the ratio of tetrahydrobiopterin (BH4) to BH2 in pancreatic ductal adenocarcinomas (PDACs). The reduced BH4/BH2 ratio leads to an increase in reactive oxygen species (ROS) generation and a decrease in the distribution of H3K27me3 at CXCL1 promoter. Consequently, myeloid-derived suppressor cells are recruited to tumor microenvironment via CXCR2 causing resistance to ICB therapy. We discovered that BH4 supplementation is capable to restore the BH4/BH2 ratio, enhance anti-tumor immunity, and overcome ICB resistance in QDPR-deficient PDACs. Tumors with lower QDPR expression show decreased responsiveness to ICB therapy. These findings offer a novel strategy for selecting patient and combining therapies to improve the effectiveness of ICB therapy in PDAC. [Display omitted] • QDPR deficiency drives immune suppression in pancreatic cancer • QDPR deficiency leads to ICB resistance via biopterin metabolic pathway • QDPR could serve as a predictive biomarker for ICB therapy in PDAC • BH4 supplementation sensitizes QDPR-deficient PDAC models to ICB The critical roles and mechanisms of biopterin metabolism in resistance to immune checkpoint blockade (ICB) therapy remain unknown. Liu et al. demonstrate the interplay between tumor-cell-hijacked biopterin metabolism and tumor immunity in PDAC and propose that QDPR deficiency causes ICB resistance in PDAC. [ABSTRACT FROM AUTHOR]