A new strategy for CAR-T therapy in solid tumors: IL-15-autocrine signaling augments tumor stroma depletion and promotes a TSCM subset in the TME

Abstract Although chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable therapeutic effects in treating hematologic cancers, its effectiveness in solid tumors remains significantly restricted. the primary reason is the immunosuppression mediated by the tumor microenvironment (TME), which leads to rapid exhaustion of infiltrating CAR-T cells. To enhance CAR-T cell efficacy against solid tumors, we pursued improvements in two aspects. First, we constructed fibroblast activation protein (FAP)-directed CAR-T cells to enhance their anti-CAF capability within the TME, thereby alleviating the immunosuppressive barrier. Second, we utilized IL-15, an efficient activator of CAR-T cells that inhibits activation-induced cell death, restores effector functions, and increases the proportion of the T stem cell memory (T SCM ) subpopulation. In this study, we report the generation of FAP/IL-15 CAR-T cells, which target FAP and autonomously synthesize and secrete IL-15. Our data demonstrate that treatment with FAP/IL-15 CAR-T cells exhibited stronger activation characteristics in a FAP antigen-dependent manner, selectively targeting CAFs within the solid TME. Moreover, endogenous IL-15 secretion enabled CAR-T cells to adopt a T SCM -like phenotype with enhanced memory characteristics, thus improving cell survival, proliferation, activation, and therapeutic efficacy against solid tumors.