Figure 3.

Gene modification strategies for CAR-T cells. A Targeting immune suppressive cells. CAR-T cells exhibit enhanced persistence and proliferation by targeting MDSCs or depleting Tregs. Likewise, repolarizing MDSCs and TAMs from an immunosuppressive to pro-inflammatory phenotype could boost the anti-tumor functions of CAR-T cells. B Targeting cytokines milieu. CAR-redirected T-cell engineered to release inducible IL-12 or IL-18 could eliminate the antigen-loss cancer cells, recruit immune cells and reinforce their functions, and sustain pro-inflammatory responses. An alternative strategy to counteract immunosuppressive TME is to generate an inverted cytokine receptor in which the IL-4 receptor exodomain was fused to the IL-7 receptor endodomain, which removes the side effects of the immunosuppressive cytokine IL-4. C Targeting chemokines milieu. CXCR1 or CXCR2-modified CARs remarkably favored T-cell migration and persistence in TME, leading to the induction of complete tumor regression and durable immunologic memory. IL-7 and CCR2b co-expressing CAR-T cells also boosted the self-survival and migration, increased IFN-γ, Gzms-B, and IL-2 expression, and inhibited tumor growth. D Targeting immune checkpoints. Blocking immune checkpoints sponsored CAR-T cell survival and function of killing tumor cells. Dominant-negative receptors (DNRs) could interfere with the PD-1/PD-L1 pathway, thereby restoring the cytotoxic and cytokine secretion functions of CAR-T cells.