The network of blood vessels in the tumour microenvironment remains one of the most difficult blockages for cell therapies to penetrate and treat solid tumours. However, a new study published in Nature Cancer explains that researchers at Penn Medicine found that combining CAR T cell therapy with a PAK4 inhibitor drug allowed modified cells to work their way through and attack the tumour, leading to significantly improved survival in mice. The genetic reprogramming of tumour endothelial cells lining the walls of blood vessels is caused by an enzyme known as PAK4. Penn’s team discovered that this enzyme reduces abnormal tumour vascularisation and improves T cell infiltration and CAR T cell immunotherapies in mouse models of glioblastoma. An experiment with T-RCA cell therapy led by EGFRvIII and a PAK4 inhibitor showed a nearly 80 percent reduction in tumour growth compared to mice that received CAR T cell therapy only five days after infusion. The targeting of PAK4 may therefore provide a unique opportunity to recondition the tumour microenvironment and improve T-cell–based cancer immunotherapy for solid tumours.