REPROGRAMMING CAR T CELLS THROUGH ECTOPIC IL-9 SIGNALING TO ENHANCE EFFICACY AGAINST SOLID TUMORS

Cancer is a leading cause of mortality worldwide, with solid tumors accounting for over 90% of all diagnosed cases. Chimeric antigen receptor (CAR) T cell therapies have emerged as a promising form of immunotherapy, harnessing the patient’s immune system to attack cancer cells. While CAR T cells have achieved durable remissions in hematologic malignancies, their efficacy against solid tumors remains limited. Compared with blood cancers, solid tumors pose unique challenges to treatment, including poor in vivo expansion and persistence, terminal differentiation, and dysfunction of CAR T cells within the immunosuppressive tumor microenvironment. One strategy to overcome these barriers is the use of cytokine receptor signaling to reprogram CAR T cell function. In this study, we demonstrate that engineering CAR T cells to co-express an ectopic interleukin-9 receptor (IL-9R) rewires CAR T cell fate under antigen stress to enhance antitumor efficacy. In preclinical solid tumor models, IL-9-signaling CAR T cells showed increased expansion, persistence, and tumor infiltration, resulting in superior tumor control at significantly lower doses than conventional CAR T cell products. Single-cell RNA sequencing coupled with trajectory and RNA velocity analyses revealed that IL-9 signaling alters CAR T cell differentiation under antigen stress, supporting a transition toward CD8+ memory and effector phenotypes and promoting a proliferative CD4+ cell state. Transcription factor analysis further identified IL-9-mediated activation of STAT1 and STAT4 as a potential driver of this enhanced phenotype. Together, these findings highlight IL-9 signaling as a promising strategy to overcome the limitations of CAR T cell therapy for solid tumors.