DYRK1A enhances antitumor immunity in type 1 conventional dendritic cells via mTORC1 activation

Type 1 conventional dendritic cells (cDC1s) play an integral role in mediating immune responses and maintaining homeostasis, yet the molecular mechanisms underlying their functions remain poorly understood. In this study, we identify dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) as a key kinase that responds to TLR and growth factor stimulation, acting as an essential regulator of cDC1 function. Genetic ablation of Dyrk1a specifically in cDC1s impairs antitumor immunity and accelerates tumor progression in murine models. Mechanistically, DYRK1A mediates the phosphorylation of the mTORC1 inhibitor TSC2 at serine 540, triggering the degradation of TSC2 and promoting the mTORC1 signaling in cDC1s. Notably, Tsc2 deletion in Dyrk1a-deficient cDC1s remarkably restores their antitumor immune functions. Furthermore, DYRK1A-mediated mTORC1 signaling in cDC1s positively correlates with effector T-cell responses across multiple human cancers. Our findings highlight a critical role for the DYRK1A-TSC2-mTORC1 signaling pathway in regulating cDC1 functions in antitumor immunity, offering potential strategies to improve cancer immunotherapy.