IRE1α and its downstream XBP1 signal is the most conserved unfolded protein response pathway that cells utilize to combat endoplasmic reticulum stress, also known to be utilized by tumor cells to adapt to harsh environment, leading to tumor progression. Several inhibitors against IRE1α have been developed, some of which show promising effect in clinical trial for cancer therapy, but none of them have been used in practice. Considering that hyper-activation of IRE1α induces cell death, we hypothesize that activation of IRE1α could be an alternative way for tumor suppression. Here, we identified divalent manganese ion as a potent activator to IRE1α, which interacts with the cytosolic part of IRE1α directly, augmenting the downstream pro-apoptotic pathway but not the pro-survival outcome. Mn(2+) limits tumor growth in xenograft model in an IRE1α-dependent way. Our finding suggests pharmacological activation of IRE1α as an underestimated but promising way in cancer therapy.