Multidrug-resistant , a prevalent opportunistic pathogen in hospitals, presents a substantial risk to immunocompromised patients, triggering life-threatening conditions including pneumonia, bacteremia, and sepsis, which can be fatal. Therefore, it is urgent to develop new therapeutic strategies to combat and eradicate multidrug-resistant infection. Our finding reveals that promotes the mice treated with 5-fluorouracil (5-FU) to defend against multidrug-resistant infection via the mTORC1-IFN-I signaling pathway. Mechanistically, triggers mTORC1 activation through the phosphorylation of p38 MAPK, and mTORC1 is required for the subsequent activation of IFN-I signaling pathways in response to treatment. studies have demonstrated that enhances the clearance of in mice subjected to 5-FU chemotherapy, with this effect being mediated through the mTORC1 signaling pathway. Our study provides insight into the therapeutic intervention of enhancing IFN-I signaling and boosting host defense against bacterial infections via the administration of .