IL-9 信号将 CAR-T 细胞命运重定向至 CD8⁺ 记忆状态和 CD4⁺ 增殖状态，增强抗肿瘤疗效

The success of chimeric antigen receptor (CAR) T cell therapies targeting solid tumors is limited by the immunosuppressive tumor microenvironment.

We demonstrate that endowing CAR T cells with ectopic interleukin (IL)-9 signaling by co-expressing an IL-9 receptor rewires CAR T cell fate under antigen stress to enhance antitumor efficacy. In preclinical solid tumor models, IL-9-signaling CAR T cells exhibit increased expansion, persistence, and tumor infiltration, resulting in superior tumor control at substantially lower doses than conventional products.

Trajectory and RNA velocity analyses of single-cell RNA sequencing data reveal that IL-9 signaling alters CAR T cell differentiation under antigen stress away from dysfunction, favoring a multipotent transition toward CD8 + T cell memory and effector states and promoting a CD4 + cell proliferative state. Interrogation of transcription factor pathways indicates that IL-9-mediated activation of STAT1 and STAT4 may contribute to the superior phenotype of IL-9-signaling CAR T cells, providing a promising therapeutic strategy for targeting solid cancers.