Driving CAR therapies beyond T cells.

Abstract

Chimeric antigen receptor (CAR)-T cell therapy has reshaped cancer immunotherapy for hematological malignancies, yet progress in solid tumors remains limited. Physical barriers, antigen heterogeneity, and immunosuppressive tumor microenvironment restrict the activity and persistence of CAR-T cells, while safety concerns complicate target selection. Extending CAR technology to alternative immune lineages, such as macrophages, natural killer cells, tumor-infiltrating lymphocytes, and unconventional T cells, offers complementary mechanisms for tumor recognition, infiltration, and immune modulation. This review highlights recent advances in these emerging CAR platforms, compares their biological and translational features, and outlines how integrating cell-intrinsic properties with CAR design may guide the next generation of cellular immunotherapies for solid tumors.