02385nas a2200313   4500000000100000000000100001008004100002653002500043653001900068653003000087653001800117653002000135100001600155700001300171700001600184700001500200700001400215700001600229700001800245700001500263700001400278700001900292245012600311856006700437300001200504490000800516520153300524022001402057                                       d10acancer immunotherapy10aDrug screening10amesenchymal stromal cells10amicrofluidics10atumor organoids1 aZhengyu Zou1 aZhun Lin1 aChenglin Wu1 aJizhou Tan1 aJie Zhang1 aYanwen Peng1 aKunsong Zhang1 aJiaping Li1 aMinhao Wu1 aYuanqing Zhang00aMicro-Engineered Organoid-on-a-Chip Based on Mesenchymal Stromal Cells to Predict Immunotherapy Responses of HCC Patients  uhttps://onlinelibrary.wiley.com/doi/abs/10.1002/advs.202302640  a23026400 vn/a3 aHepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide. Patient-derived organoid (PDO) has great potential in precision oncology, but low success rate, time-consuming culture, and lack of tumor microenvironment (TME) limit its application. Mesenchymal stromal cells (MSC) accumulate in primary site to support tumor growth and recruit immune cells to form TME. Here, MSC and peripheral blood mononuclear cells (PBMC) coculture is used to construct HCC organoid-on-a-chip mimicking original TME and provide a high-throughput drug-screening platform to predict outcomes of anti-HCC immunotherapies. HCC-PDOs and PBMC are co-cultured with MSC and Cancer-associated fibroblasts (CAF). MSC increases success rate of biopsy-derived PDO culture, accelerates PDO growth, and promotes monocyte survival and differentiation into tumor-associated macrophages. A multi-layer microfluidic chip is designed to achieve high-throughput co-culture for drug screening. Compared to conventional PDOs, MSC-PDO-PBMC and CAF-PDO-PBMC models show comparable responses to chemotherapeutic or targeted anti-tumor drugs but more precise prediction potential in assessing patients’ responses to anti-PD-L1 drugs. Moreover, this microfluidic platform shortens PDO growth time and improves dimensional uniformity of organoids. In conclusion, the study successfully constructs microengineered organoid-on-a-chip to mimic TME for high-throughput drug screening, providing novel platform to predict immunotherapy response of HCC patients.  a2198-3844