IRE1α–XBP1s signaling links lipid homeostasis to hypoxic maladaptation and KRAS inhibitor responses in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is among the most hypoxic human tumors. Because fatty acid (FA) desaturation is oxygen-dependent, hypoxia can limit monounsaturated FA (MUFA) production, increase membrane lipid saturation, and activate endoplasmic reticulum stress responses, including IRE1α-XBP1s. Here, we found that under oxygen- and MUFA-limiting conditions, spliced XBP1 (XBP1s) is upregulated but unexpectedly exerts a cytotoxic rather than cytoprotective role in PDAC cells. This effect did not differ substantially between classical and basal subtypes. In contrast, pharmacologic or genetic XBP1s inhibition had limited effects on tumor growth and apoptosis in vivo, suggesting this cytotoxicity is largely bypassed by factors in the tumor microenvironment. Consistent with our previous findings that cancer-associated fibroblasts supply unsaturated lipids to tumor cells, subcutaneous tumors showed abundant alpha-smooth muscle actin (α-SMA)-positive stroma, supporting the possibility that stromal lipid supply protects tumors from XBP1s-dependent lipotoxicity. Although XBP1s expression increased during PDAC progression, its distribution remained focal and heterogeneous within human tumors, suggesting spatially restricted IRE1α-XBP1s pathway activation that may limit the efficacy of monotherapy in patients. However, MRTX1133-resistant PDAC became more susceptible to IRE1α-XBP1s targeting, and MRTX1133 acutely activated this pathway in parental cells upon treatment. Importantly, the IRE1α RNase inhibitor B-I09 clearly synergized with MRTX1133 in vitro and in vivo, moreover, this is likely due to MYC-fatty acid synthase (FASN) dysregulation. Together, these findings identify context-dependent vulnerabilities of the IRE1α-XBP1s pathway in PDAC and provide a rationale for combining inhibition of IRE1α and KRAS to enhance therapeutic responses.