The mannosyltransferase DPM1 regulates the activity of ER-stress sensor IRE1 in colorectal cancer.

Most colorectal cancer (CRC) patients exhibit resistance to immune checkpoint blockade (ICB), limiting treatment efficacy. Activating the unfolded protein response sensor IRE1α in cancer cells can induce anticancer immune responses, yet its regulation remains unclear. Here we identify Dolichyl-Phosphate Mannosyltransferase 1 (DPM1) as a regulator of IRE1 expression and activity using BioID screen. Analysis of CRC patient RNA-sequencing data reveals that low DPM1 expression correlates with an IRE1-dependent transcriptional signature, increased immune infiltration, and improved ICB responses. Mechanistically, DPM1 ablation reduces protein glycosylation, causing chronic IRE1 activation in cancer cells and enhanced cytotoxic T cell-mediated immunosurveillance. Inhibition or knock-out of IRE1 reverses this effect. These findings establish DPM1 as a modulator of IRE1 activity that influences tumor immunogenicity, suggesting its potential as a therapeutic target to improve cancer immunotherapy outcomes.