ERN1 and neoplasm: Collectively, our work demonstrates for the first time that the uncoupling of XBP1s and RIDD signals downstream of IRE1 impacts on cancer development and points toward an alternative therapeutic avenue coupled with personalized molecular diagnosis for (i) decreasing tumor cells’ adaptive properties, (ii) enhancing RNA catabolic pathways leading to accelerated tumor cell death, and (iii) modulating the tumor stroma through reduced angiogenesis and increased anti‐tumor immunity.