Navigating CAR-T cells through the solid-tumour microenvironment

The adoptive transfer of T cells that are engineered to express chimeric antigen receptors (CARs) has shown remarkable success in treating B cell malignancies but only limited efficacy against other cancer types, especially solid tumours. Compared with haematological diseases, solid tumours present a unique set of challenges, including a lack of robustly expressed, tumour-exclusive antigen targets as well as highly immunosuppressive and metabolically challenging tumour microenvironments that limit treatment safety and efficacy. Here, we review protein- and cell-engineering strategies that seek to overcome these obstacles and produce next-generation T cells with enhanced tumour specificity and sustained effector function for the treatment of solid malignancies. Chimeric antigen receptors (CARs) have shown limited efficacy in the treatment of solid tumours. In this Review, Chen and colleagues discuss various engineering strategies to overcome the obstacles that the tumour microenvironment poses to CAR-T cells, to produce next-generation T cells with enhanced specificity and sustained function for the treatment of solid tumours.