biostudies-literatureCrowley MJPNCATS NIH HHSUnited States Department of Defense | United States Army | Army Medical Command | Congressionally Directed Medical Research ProgramsNCI NIH HHSNINDS NIH HHSU.S. Department of Health & Human Services | National Institutes of Health120https://www.ebi.ac.uk/biostudies/studies/S-EPMC9829901biostudies-literatureUnknown14(1)IRE1α-XBP1 signaling is emerging as a central orchestrator of malignant progression and immunosuppression in various cancer types. Employing a computational XBP1s detection method applied to TCGA datasets, we demonstrate that expression of the XBP1s mRNA isoform predicts poor survival in non-small cell lung cancer (NSCLC) patients. Ablation of IRE1α in malignant cells delays tumor progression and extends survival in mouse models of NSCLC. This protective effect is accompanied by alterations in intratumoral immune cell subsets eliciting durable adaptive anti-cancer immunity. Mechanistically, cancer cell-intrinsic IRE1α activation sustains mPGES-1 expression, enabling production of the immunosuppressive lipid mediator prostaglandin E₂. Accordingly, restoring mPGES-1 expression in Nature communicationsTumor-intrinsic IRE1α signaling controls protective immunity in lung cancer.PMC9829901F31 CA217032UL1 TR002384CA217032-01LC180486R21 CA248106KL2 TR002385R01 NS114653McGraw TEHu YElemento OCrowley MJPChopra SAltorki NKGao DTavarez DAVerma ACubillos-Ruiz JRYomtoubian SMittal VSandoval TAGiovanelli PChae CSBhinder BMartin MMarkowitz GJfalseTumor-intrinsic IRE1α signaling controls protective immunity in lung cancer.IRE1α-XBP1 signaling is emerging as a central orchestrator of malignant progression and immunosuppression in various cancer types. Employing a computational XBP1s detection method applied to TCGA datasets, we demonstrate that expression of the XBP1s mRNA isoform predicts poor survival in non-small cell lung cancer (NSCLC) patients. Ablation of IRE1α in malignant cells delays tumor progression and extends survival in mouse models of NSCLC. This protective effect is accompanied by alterations in intratumoral immune cell subsets eliciting durable adaptive anti-cancer immunity. Mechanistically, cancer cell-intrinsic IRE1α activation sustains mPGES-1 expression, enabling production of the immunosuppressive lipid mediator prostaglandin E₂. Accordingly, restoring mPGES-1 expression in 2023-01-01T00:00:00Z2023 Jan2026-07-14T17:03:40.052Z2025-04-19T23:08:13.209ZS-EPMC98299013662409310.1038/s41467-022-35584-9