Dendritic cells (DCs) are classically viewed as chief sentinels of immunity, yet how their functional states are molecularly encoded remains incompletely understood. IRE1, the most evolutionarily conserved sensor of the unfolded protein response (UPR), is a bifunctional enzyme with kinase and an endoribonuclease (RNase) activity that controls gene expression through two distinct outputs: the splicing and activation of the transcription factor XBP1s, and regulated RNA decay (RIDD). Interestingly, emerging evidence indicates that IRE1 functions not merely as a stress sensor, but as an instructive node that actively programs DC function, with pronounced and subset-specific roles in type 1 conventional DCs (cDC1).

Here, I will present data indicating that IRE1 RNase activity integrates environmental and metabolic cues to regulate functional states in DCs. This regulation is tissue-imprinted: in the intestine, we uncovered that there is an elevated DC-intrinsic IRE1 activity that governs tissue immunosurveillance, epithelial barrier integrity, and type 3 immune activation thresholds.

Furthermore, we demonstrate that IRE1 signaling through these dual RNase outputs can be selectively engaged, enabling context-dependent rewiring of DC function. Using novel tools to partially inhibit and titrate IRE1 RNase activity, we resolve how these outputs differentially control cDC1 programming, cellular fitness, and survival, uncovering a previously unappreciated layer of regulation in DC specialization.

Collectively, these findings redefine the UPR as an active driver of DC biology and position IRE1 as a tunable molecular switch at the interface of stress sensing and immunity, with implications for therapeutic targeting in inflammatory and barrier-associated diseases.