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.

生物蝶呤代谢与免疫检查点阻断（ICB）治疗抵抗的相关性仍不清楚。我们证明，奎宁二氢蝶啶还原酶（QDPR）是调节生物蝶呤代谢的关键酶，其缺乏会导致代谢物二氢生物蝶呤（BH2）积累，并降低胰腺导管腺癌（PDAC）中四氢生物蝶呤（BH4）与BH2的比例。 BH4/BH2 比率降低会导致活性氧 (ROS) 生成增加以及 CXCL1 启动子处 H3K27me3 分布减少。因此，骨髓来源的抑制细胞通过 CXCR2 被招募到肿瘤微环境中，导致对 ICB 治疗产生耐药性。我们发现补充 BH4 能够恢复 BH4/BH2 比例，增强抗肿瘤免疫力，并克服 QDPR 缺陷的 PDAC 中的 ICB 耐药性。 QDPR 表达较低的肿瘤对 ICB 治疗的反应性降低。这些发现为选择患者和联合治疗以提高 PDAC 中 ICB 治疗的有效性提供了一种新策略。