Synthetic biology has been transformative to the treatment of advanced hematological malignancies by chimeric antigen receptor (CAR)-engineered T cells. A range of obstacles are now understood to limit the responses of solid epithelial-derived tumors to CAR therapy. For example, inefficient tumor homing and a fortified stroma can restrain the number of CAR-T cells reaching the tumor bed. Upon transendothelial migration across the tumor vasculature, CAR-T cells face a highly suppressive microenvironment that can quickly render them hypofunctional. Safety also remains a critical issue for advancing CAR therapy of solid tumors. Innovative CAR design as well as coengineering and combinatorial treatment strategies with oncolytic adenovirus, radiotherapy, vaccines, chemotherapy, small molecules and monoclonal antibodies hold tremendous potential to support CAR-T cell control of solid tumors, either by directly promoting CAR-T cell function, or/and by re-programming the TME and harnessing the endogenous immune system against the tumor.