Enhancement of the antitumor effect of HER2‐directed CAR‐T cells through blocking epithelial‐mesenchymal transition in tumor cells

The efficacy of chimeric antigen receptor T (CAR‐T) cell therapy in solid tumors is far from satisfactory. In this study, we investigated the influence of epithelial‐mesenchymal transition (EMT) on the antitumor effect of CAR‐T cells and explored the potential efficacy of combining CAR‐T cells with inhibitors targeting EMT. We successfully induced EMT in tumor cells with TGF‐β1, and the antitumor effect of HER2‐directed CAR‐T cells was significantly suppressed by EMT. Upregulation of PD‐L1 was observed in tumor cells undergoing EMT, and change in PD‐L1 expression during the EMT process was dependent on the MEK/ERK and PI3K/Akt pathways. Inhibition of the TGF‐β1 pathway could block the EMT process in tumor cells and restore their susceptibility to HER2‐directed CAR‐T cells in vitro. In addition, targeting the TGF‐β1 pathway significantly enhanced the antitumor effect of HER2‐directed CAR‐T cells in vivo. Our findings suggest that blocking EMT could potently enhance the antitumor effect of CAR‐T cells, which provides a promising approach to improving the therapeutic efficacy of CAR‐T cell therapy in solid tumors.