Fig. 4

Gene modification strategies for next-generation CAR T cells. a Improving CAR T cell antigen recognition: Bi-specific CAR (TanCAR) T cells that target two different TAAs display superior antigen-recognition ability. Universal CAR T cells(UniCAR) and CART.BiTE (BiTE.CAR) utilize adapters connecting CAR T cells and tumor cells, to target multiple antigens. b Enhancing CAR T cell proliferation and persistence: C7R activates the downstream IL-7 signaling pathway without the participation of exogenous cytokine. The 28-IL2RB-z(YXXQ) CAR activates the JAK/STAT signaling pathway after antigen engagement, by introducing IL-2Rβ and the tyrosine-X-X-glutamine (YXXQ) motif. Inducible cytokine-secreting CAR T cells release cytokines upon CAR recognition of the tumor-specific antigen. Incorporating costimulatory molecules, such as TLR2 and DAP10, into the 3′ end of CAR augments costimulatory signaling in CAR T cells. c Increasing CAR T cell trafficking to the tumor site: The expression of chemokine receptor like CXCR2 in CAR T cells enhances their migratory ability towards tumor-derived chemokines. CAR T cells targeting FAP or expressing heparanase can disrupt physical barriers to increase CAR T cell infiltration. d Overcoming CAR T cell dysfunction: Chimeric switch receptors (CSRs), such as 4/7 ICR and PD-1/CD28, transform negative signaling into positive signaling by modifying the receptor endodomain. Dominant-negative receptors (DNRs) without transmembrane or intracellular signaling domains block negative signaling mediated by PD-1. Knocking out the PD-1 gene using gene-editing technology, such as CRISPR/Cas9, can block the suppression signal in CAR T cells