Evaluation of anti-tumor drugs by simulating physiological absorption and metabolism with a multi-organoid system

Although patient-derived tumor organoids are widely applied for evaluating anti-tumor drugs, the lack of a physiologically relevant environment limits drug assessment. Intestinal absorption and liver metabolism are critical for drug efficacy but cannot be recapitulated in single-organoid models. Here, we establish an intestine-liver-tumor multi-organoid system to simulate in vivo absorption and metabolism, which allows for more physiologically relevant evaluations of drug efficacy and toxicity. Under fluidic conditions, the system maintains the viability of intestinal cells and liver organoids, which exhibit superior cellular diversity and close transcriptional resemblance to native tissues, with enhanced differentiation and metabolism. The system reveals the decreased effectiveness of the liver-deactivated drugs docetaxel and 5-FU, and the increased efficacy of the liver-activated drugs capecitabine and ifosfamide, on tumor organoids, which cannot be revealed by tumor organoid models alone. With gravity-driven flow and multi-organ interactions, this system recapitulates drug absorption and metabolism, thus providing a platform for accurate evaluations of metabolism-dependent drugs and advancing precision medicine.