A research team from the University of Pennsylvania has developed a lung cancer chip model containing living blood vessels, providing a new platform for dissecting the mechanisms of CAR-T cell therapy in solid tumor treatment. Published in Nature Biotechnology, this study simulates the tumor microenvironment to reveal the interactions between immune cells and cancer cells.

Professor Dan Dongeun Huh in Bioengineering stated: "CAR-T cell therapy has achieved remarkable success in blood cancers, but its effectiveness is limited for solid tumors, which account for over 90% of all cancers. The primary challenge lies in overcoming the defensive mechanisms of the tumor microenvironment." The tumor chip model uses transparent microengineered devices to construct a three-dimensional culture system containing human lung cancer cells and vascular networks.

Postdoctoral researcher Haijiao Liu said: "We aimed to create an environment where tumor cells exhibit their true in vivo behavior. By reconstructing the tumor microenvironment, we can observe the mechanisms of cell-to-cell interactions." The team discovered that tumor vascular endothelial cells release chemotactic signals, but these signals are short-lived. By adding the diabetes drug vildagliptin, the duration of the signals can be effectively prolonged, enhancing CAR-T cell recruitment to the tumor region.

The researchers combined multi-omics technologies and bioinformatics to deeply analyze the molecular biology of CAR-T cells in the tumor microenvironment. They identified that DPP4 enzymes produced by fibroblasts and T cells degrade chemotactic signals, while existing DPP4 inhibitors can restore communication between tumor vasculature and immune cells. Professor Huh noted: "The transparency of this system makes it a window into cancer immunotherapy, allowing clear observation of CAR-T cells moving and attacking within tumor tissue."

In experimental observations, the team recorded the entire process of individual T cells crossing the vascular wall, migrating through tissue, and attacking tumor cells. These real-time observation data provide direct evidence for improving CAR-T cell design. The application of this tumor chip model is expected to accelerate the development of novel immunotherapies while reducing reliance on animal experiments.

Huh emphasized: "The high physiological fidelity of the model enables us to obtain clinically relevant high-dimensional data. These mechanistic insights will help develop safer and more effective cancer immunotherapy strategies."