Nuanced role for dendritic cell intrinsic IRE1 RNase in the regulation of antitumor adaptive immunity

The IRE1/XBPls axis of the unfolded protein response (UPR) plays divergent roles in dendritic cell (DC) biology in steady state versus tumor contexts. Whereas tumor associated DCs show dysfunctional IRE1/XBP1s activation that curtails their function, the homeostasis of conventional type 1 DCs (cDC1) in tissues requires intact IRE1 RNase activity. Considering that cDC1s are key orchestrators of antitumor immunity, it is relevant to understand the functional versus dysfunctional roles of IRE1/XBP1s in tumor DC subtypes. Here, we show that cDC1s constitutively activate IRE1 RNase within subcutaneous B16 melanoma and MC38 adenocarcinoma tumor models. Mice lacking XBP1s in DCs display increased melanoma tumor growth, reduced T cell effector responses and accumulation of terminal exhausted CD8⁺T cells. Transcriptomic studies revealed that XBP1 deficiency in tumor cDCls decreased expression of mRNAs encoding XBPls and regulated IRE1 dependent decay (RIDD) targets. Finally, we find that the dysregulated melanoma growth and impaired T cell immunity noticed in XBP1 deficient mice are attributed to RIDD induction in DCs. This work indicates that IREl RNase activity in melanoma/MC38-associated DCs fine tunes aspects of antitumor immunity independently of XBP1s, revealing a differential role for the UPR axis that depends on the DC subtype and cancer model.