Gene modification strategies for next-generation CAR T cells against solid cancers

Immunotherapies have become the backbone of cancer treatment. Among them, chimeric antigen receptor (CAR) T cells have demonstrated great success in the treatment of hematological malignancies. However, CAR T therapy against solid tumors is less effective. Antigen targeting; an immunosuppressive tumor microenvironment (TME); and the infiltration, proliferation, and persistence of CAR T cells are the predominant barriers preventing the extension of CAR T therapy to solid tumors. To circumvent these obstacles, the next-generation CAR T cells will require more potent antitumor properties, which can be achieved by gene-editing technology. In this review, we summarize innovative strategies to enhance CAR T cell function by improving target identification, persistence, trafficking, and overcoming the suppressive TME. The construction of multi-target CAR T cells improves antigen recognition and reduces immune escape. Enhancing CAR T cell proliferation and persistence can be achieved by optimizing costimulatory signals and overexpressing cytokines. CAR T cells equipped with chemokines or chemokine receptors help overcome their poor homing to tumor sites. Strategies like knocking out immune checkpoint molecules, incorporating dominant negative receptors, and chimeric switch receptors can favor the depletion or reversal of negative T cell regulators in the TME.