Using chimeric antigen receptor (CAR) T cell therapy in solid tumours requires effective T cell tumour infiltration and functional persistence. Adusumilli et al. have found that, in an orthotopic model of lung cancer, administering mesothelin-targeted CAR T cells directly to the lung required fewer cells and achieved longer-term remission than doing so intravenously. This therapeutic efficacy was dependent on early activation of CD4+ T cells and CD28-dependent CD4+ T cell-mediated cytotoxicity, and was also effective at eliminating tumours in extrathoracic, disseminated sites.