胰腺癌（PC）的生存率低且预后不良。我们发现，在固有免疫细胞中主要表达的卡司培替结构域含9（CARD9）蛋白的表达与PC患者的预后呈正相关。CARD9缺陷的PC小鼠表现出更快的癌症进展和更差的生存率。CARD9缺陷降低了树突状细胞（DC）的成熟度，在体内和体外障碍了DC激活T细胞的能力。养育DC输注验证了CARD9缺陷在PC中依赖于DC。肌酸被鉴定为WT DC和CARD9-/- DC之间最显著的差异代谢产物，其在维护DC成熟和功能中发挥了关键作用。CARD9缺陷通过抑制肌酸特异性转运体溶质载体家族6成员8（SLC6A8）的转录，导致DC中肌酸水平降低。CARD9的进一步缺失通过废除CARD9-BCL10-MALT1复合物的形成，阻止了p65和SLC6A8启动子之间的结合，从而阻塞了p65的激活。这些事件降低了肌酸进入DC的转运，导致DC未成熟和抗肿瘤免疫功能受损，进而促进了PC的进展。© 2023作者。由Taylor＆Francis Group，LLC许可发布。

Pancreatic cancer (PC) is featured with low survival rate and poor outcomes. Herein, we found that the expression of caspase-recruitment domain-containing protein 9 (CARD9), predominantly expressed in innate immune cells, was positively related to the prognosis of PC patients. CARD9-deficient PC mice exhibited rapider cancer progression and poorer survival rate. CARD9 knockout decreased dendritic cell (DC) maturation and impaired DC ability to activate T cells in vivo and in vitro. Adoptive DC transfer confirmed that the role of CARD9 deficiency in PC relied on DCs. Creatine was identified as the most significant differential metabolite between WT DCs and CARD9-/- DCs wherein it played an essential role in maintaining DC maturation and function. CARD9 deficiency led to decreased creatine levels in DCs by inhibiting the transcription of the creatine-specific transporter, solute carrier family 6 member 8 (SLC6A8). Furtherly, CARD9 deletion blocked p65 activation by abolishing the formation of CARD9-BCL10-MALT1 complex, which prevented the binding between p65 and SLC6A8 promoter. These events decreased the creatine transport into DCs, and led to DC immaturity and impairment in antitumor immunity, consequently promoting PC progression.© 2023 The Author(s). Published with license by Taylor & Francis Group, LLC.