Fig. 2

Novel strategies to enhance the efficacy of CAR-T cell therapy for solid tumors. a CAR-T cells targeting tumor specific antigens. b Infiltration and homing of CAR-T cells. CAR-modified T cells express a chemokine receptor (e.g., CCR2b or CCR4), increasing their ability to move to the tumor site. FAP-specific CAR-T cells can migrate to the tumor bed, similar to integrin αvβ3 (or αvβ6)-specific CAR-T cells. Heparanase expression enhances CAR-T cell infiltration and antitumor activity. c CAR-T cells secreting cytokines or enzymes. To resist a hostile environment, T cells have been engineered to express cytokines, such as IL-12 or IL-15. CAR-T cells are endowed with the catalase to overcome abundant ROS. CAR-T cells carrying soluble HVEM also enhance therapeutic activity against lymphomas. d CAR-T cells expressing receptors. CAR-T cells expressing costimulatory receptors (e.g., 4/1BBL or CD40L) significantly enhance T cell activity. CAR-T cells expressing a hybrid receptor comprising an IL-4 exodomain and IL-7 endodomain convert the immunosuppressive response to immune action by targeting IL-4. CAR-T cells expressing IL-7Rα specific for IL-7 have improved response in solid tumors. T cells with a dominant-negative TGFβ (DN TGF-βR) response to TGFβ. e Immune checkpoint therapy. CAR-T cell therapy can be combined with the blockage of immune checkpoints using monoclonal antibodies or the CRISPR/Cas9 system. Additionally, PD1:CD28 CAR comprising the PD1 exodomain and CD28 endodomain enhance T cell activity. f Other blockage therapies. Blockage of soluble tumor suppressive mediators in the solid tumor milieu (e.g., CD73, A_2AR, IDO, or CD47) enhance CAR-T cell function. g Combination therapies. CAR-T cells can be combined with other antitumor strategies, such as oncolytic viruses, HIF-CAR, exosomes, nanoparticles, and modulating T cell metabolism