Abstract

Pancreatic cancer (PC) cells suppress dendritic cell (DC) maturation and function through multiple pathways, further impairing antitumor activity of CD8 + T cells. Our previous study revealed that caspase-recruitment domain-containing protein 9 (CARD9) deficiency led to DC dysfunction and exacerbated PC progression, yet the precise mechanism underlying CARD9 downregulation in DCs remains elusive. In this study, we observed that CARD9 expression was progressively downregulated in PC tumors and associated with advanced clinicopathological stages and DC dysfunction. Functionally, PC cells reduced CARD9 expression, impaired DC maturation and weakened CD8 + T cell activation, with these suppressive effects attenuated in CARD9-deficient DCs and reversed when CARD9 was restored. Then, we identified YY1 as a critical upstream transcription factor that bound to the promoter of CARD9 and repressed it, accompanied with DC dysfunction and tumor growth. Mechanistically, tumor-derived lactate induced YY1 lactylation at lysine 183, facilitating YY1 nuclear entry and strengthening its combination with CARD9 promoter. Furthermore, we identified p300 as the “writer” catalyzing YY1-K183 lactylation, and HDAC2 as its enzymatic “eraser”. Lactylation enhanced YY1 stability by limiting ubiquitination, sustaining YY1 activation and reinforcing CARD9 suppression. Overall, our findings define a lactate-p300/HDAC2-YY1 lactylation-CARD9 regulatory axis that restricts DC function and promotes immune escape in PC.