Biomechanically primed liver microtumor array as a high-throughput mechanopharmacological screening platform for stroma-reprogrammed combinatorial therapy.

Recent breakthrough in stroma-reprogrammed combinatorial therapy (SRCT) for pancreatic tumor opens a new route for improving conventional chemotherapeutic efficacy, which utilizes VDR ligand to reprogram activated stromal cells in stiffened microenvironment, leading to reduced 'barrier effects' and increased tissue-infiltration of the chemotherapy drug. As a novel therapeutic strategy and mechanism of action, the progress of SRCT relies on tailored in vitro drug assessment platforms to further optimize its efficacy and extend to applications in other tumor types. Here, a high-throughput mechanopharmacological drug screening platform for SRCT was established based on biomechanically primed hepatic stromal stellate cells to recapitulate state-specific liver microtumors with barrier effects. Fifteen generic chemotherapy drugs co-administered with VDR ligand were screened to obtain optimal SRCT formulations (e.g. carboplatin + calcipotriol), which efficacy was successfully verified in xenograft tumor models. Overall, this platform provides a powerful tool for discovery and optimization of tissue-specific SRCT and realizes 'mechanopharmacology' to translate insights of stromal mechanobiology to pharmaceutical applications.