Synergistic Combination of Oral Transcytotic Nanomedicine and Histone Demethylase Inhibitor for Enhanced Cancer Chemoimmunotherapy

Oral nanomedicines present a preferable avenue for cancer immunotherapy, but their efficacy is limited by gastrointestinal absorption challenges, tumor physiopathologic barriers, and immune evasion mechanisms. Here, we present an approach that combines an oral transcytotic doxorubicin (DOX) nanomedicine with the histone demethylase inhibitor 5-carboxy-8-hydroxyquinoline (IOX1), thereby enabling synergistic chemoimmunotherapy. We demonstrate that IOX1 significantly augments the transcytosis capabilities of DOX-loaded poly(2-(<i>N</i>-oxide-<i>N</i>,<i>N</i>-diethylamino)ethylmethacrylate)-poly(ε-caprolactone) micelles (OPDOX), promoting their transcellular transport across various cellular barriers (villus, endothelial, and tumor cells), thus improving oral adsorption, vascular extravasation, and tumor penetration. Furthermore, IOX1 sensitizes chemotherapy to potentiate DOX-induced immunogenic cell death and downregulates programmed cell death-ligand 1 to disrupt the immune checkpoint mechanism, synergistically boosting robust antitumor immune responses. Consequently, orally administered OPDOX in combination with IOX1 efficiently inhibits CT26 tumor growth, highlighting the significant potential for enhancing the efficacy of oral nanomedicines in cancer chemoimmunotherapy.