Sustained IL-15 release enhances CAR-T therapy in multiple myeloma via FOXO1 signaling axis activation.

This study developed a hypoxia-responsive N-803 nanogel (BiA-N-803 NG) for controlled release of an IL-15 superagonist to enhance CAR-T cell therapy in multiple myeloma. The nanogel was dual-targeted to CD138 and TIM-3 and exhibited stable, hypoxia-triggered release properties. In vitro analyses demonstrated that BiA-N-803 NG promoted CAR-T cell expansion, memory programming, and antitumor function, characterized by increased memory T-cell subsets and reduced exhaustion phenotypes. Transcriptomic profiling identified activation of the FOXO1 signaling axis as a key mechanism underlying CAR-T cell memory differentiation. In vivo studies further showed improved CAR-T cell persistence, enhanced NK cell recruitment, and reduced infiltration of immunosuppressive cells, collectively leading to a remodeled immune microenvironment and improved therapeutic durability in multiple myeloma.