CAR T Cells Secreting NGF-Neutralizing scFv Enhance Efficacy in Clear Cell Renal Cell Carcinoma by Relieving Immunosuppression through Immunosympathectomy [scRNA-seq]

This study investigated the role of sympathetic denervation in enhancing CAR T cell anti-tumor efficacy in renal clear cell carcinoma. By blocking the NGF pathway with antibodies, we demonstrated reduced sympathetic nerve distribution and delayed tumor progression. Furthermore, CAR T cells engineered to secrete NGF scFv achieved tumor immunosympathectomy, leading to improved anti-tumor effects. RNA sequencing revealed that this enhancement was linked to reduced terminal exhaustion in CD8 T cells and inhibited macrophage polarization from M1 to M2, promoting a robust anti-tumor immune state. Additionally, splenic T cells exhibited a stronger immune effector phenotype following the infusion of NGF scFv-secreting CAR T cells. These findings suggest that immunosympathectomy may represent a novel strategy to mitigate tumor-induced immunosuppression and improve CAR T cell efficacy in solid tumors. Overall design: Tumor cells were inoculated into the left axilla of Balb/c mice. When tumors reached approximately 80 mm3, mice were intraperitoneally injected with 200 mg/kg cyclophosphamide. Two days later, the mice were randomly divided into three groups and intravenously infused with either UT, 1×107 V28z, or 1×107 V28z/aNGF cells. 500,000 U of human recombinant IL-2 was administered intraperitoneally, followed by continuous injections twice daily for two days.