Nanotherapeutic Wee1 Inhibition Sensitizes Tumor Ferroptosis to Promote Cancer Immunotherapy and Abscopal Effect

The major issue with cancer immunotherapy is the low response rate. So, development of therapeutics enhancing immune responses is an urgent need. Tumor ferroptosis could produce immunogenic cancer cell death, which may improve cancer immunotherapy. However, current ferroptosis inducers may be limited to specific genetic backgrounds of cancer cells. Therefore, sensitization to ferroptosis inducers has also been highly pursued. Here, we found that Wee1 expression was negatively associated with drug sensitivity and positively correlated with an immunosuppressive microenvironment. Further investigation demonstrated that Wee1 inhibition could result in changes of ferroptosis and iron ion homeostasis, regardless of p53 status. Our in vitro results demonstrated the underlying mechanism that Wee1 inhibition primed cancer cells to ferroptosis through mitochondria reactive oxygen species and labile iron-dependent pathways. In order to decrease side effects, we developed an acidic responsive nanoformulation of the Wee1 inhibitor, which can sensitize tumor ferroptosis in vivo and also improve the response of cancer immunotherapy. Combining immunotherapy, nanotherapeutic Wee1 inhibition also produced abscopal effect with up to 55% mice cured that has not been seen before. In summary, nanotherapeutic Wee1 inhibition sensitized ferroptosis to enhance cancer immunotherapy and abscopal effect.