The differential mechanisms by which IRE1 signaling integrates the intensity and duration of ER stress to regulate cell fate is particularly noticed in the immune system, with cells such as cDC1s, B cells or NK cells that opt for an intact IRE1/XBP1s axis to maintain cellular health (22, 31, 45–47), and cells including TAM/MdCs or intratumoral T cells, which acquire dysfunctional phenotypes upon enforced IRE1/XBP1s activation at the tumor site (25, 28, 32). This evidence concerns the gene ERN1 and neoplasm.