Overexpression of FBP1 enhances dendritic cell activation and maturation by inhibiting glycolysis and promoting the secretion of IL33 in lung adenocarcinoma.

Fructose 1,6-diphosphatase 1 (FBP1) is an enzyme involved in gluconeogenesis and glycolysis inhibition. Dendritic cells (DCs) are antigen-presenting cells, and antigens presented to T cells activate the immune response. FBP1 inhibits the development of several tumors, and high FBP1 expression inhibits the proliferation, migration, and invasion of lung cancer cells. However, the mechanism through which FBP1 mediates the tumor immune microenvironment is unclear. This study mainly analyzed the role of FBP1 in regulating the function of DCs through metabolic reprogramming and immune microenvironment using in vitro and in vivo experiments. The positive association of FBP1 with DCs was found by bioinformatic analysis. The in vitro experiments revealed that the extracellular acidification rate and lactate level were lower in the FBP1 overexpression cells than in the control cells and that the lower lactate level reduced the inhibition of DC function. In addition, high FBP1 expression promoted the secretion of IL33 by activating the cGAS/STING/NF-κB/IL33 pathway, which was identified and verified via high-throughput sequencing and in vitro experiments. FBP1 activated the cGAS/STING pathway by increasing the degree of DNA damage, as revealed by the level of γH2AX and comet assay. IL33 enhanced the expression of the DC costimulatory molecules CD86 and HLA-DR as well as that of the functional factor IL-1β. The results demonstrated that FBP1 promoted the activation and maturation of DCs by inhibiting glycolysis and promoting the secretion of IL33 as well as by further activating the function of CD8T cells. Finally, the humanized immune system mouse models confirmed the above role of FBP1. Thus, FBP1 may serve as a new target to cure lung adenocarcinoma, and IL33 may improve the efficiency of immune therapy in lung adenocarcinoma.