Irinotecan is a widely used chemotherapeutic agent for the treatment of advanced and metastatic colorectal cancer (CRC). However, its clinical application remains unsatisfactory due to its side effects and limited efficacy. Here, we first demonstrate that irinotecan promotes liver metastasis in CRC by inducing chemotherapy-related steatohepatitis, which is an understudied side effect of irinotecan. To abrogate the prometastatic effect of irinotecan, we employ indole-3-carbinol (I3C), an aryl hydrocarbon receptor (AHR) agonist, to develop a self-assembled nanomedicine (termed NICER). NICER abolishes liver metastasis driven by irinotecan-induced steatohepatitis through activating the AHR/CPT1A axis and promoting fatty acid oxidation of hepatocytes. Importantly, NICER also significantly potentiated the antitumor effect of irinotecan. It markedly enhances cellular uptake of irinotecan via caveolin-dependent endocytosis, enabling direct delivery to the endoplasmic reticulum (ER) to induce lethal ER stress. Meanwhile, I3C encapsulated in NICER inhibits glycolysis by activation of AHR. In subcutaneous and liver metastatic CRC models, NICER demonstrates potent antitumor efficacy, reducing the tumor burden by 74.6% and 96.2%, respectively, while also exhibiting good biosafety. In summary, this work synergistically abrogates the prometastatic adverse effect of irinotecan and enhances its antitumor efficacy, presenting a promising strategy to potentiate irinotecan-based chemotherapies.
