Single-chain IL-23 secretion by CAR-T cells improves tumor control and persistence against solid tumors.

Chimeric antigen receptor (CAR)-T cell therapy achieves durable remissions in hematologic malignancies, yet its success against solid tumors is blunted in part by the tumors' highly immunosuppressive microenvironment. Fourth-generation "armored" CAR-T cells are engineered to secrete pro-inflammatory molecules to counteract this barrier. Here, we engineered TnMUC1-targeted CAR-T cells that constitutively secrete either single-chain interleukin-12 (scIL-12) or scIL-23. Both cytokine-armored CAR-T cell formats improved effector function in vitro, increasing interferon-γ production and cytotoxicity compared with their unarmored counterparts. scIL-12- and scIL23-secreting CAR-T cells significantly delayed tumor growth and prolonged survival in mouse xenograft models of human breast and prostate cancer, while scIL-23 secretion led to increases in in vivo persistence and retention of early differentiation states. These findings nominate scIL-23 armoring as a promising strategy to extend CAR-T cell therapy to solid tumors.