Spatial transcriptomics of mouse lung after tumor induction.

Here, we show that IL-12/FLT3L-armed dendritic-cell progenitors (DCPs) overcome these barriers by reprogramming the tumor microenvironment into an immune-responsive ecosystem dominated by interferon (IFN)-IRF1 signaling, which unlocked both chemo-immunotherapy and CAR-T efficacy in autochthonous and orthotopic KrasG12D;Trp53−/− lung tumors.

DCP monotherapy triggered an IFN-stimulated gene (ISG) circuit operative across cellular compartments, while combination therapy enhanced tumor regression independent of MHC-I expression in cancer cells or CD8 T cell cytotoxicity. This response involved the expansion of IFNγ⁺ T and NK cells, inflammatory monocytes, ISG-polarized neutrophils, and immune-stimulatory fibroblasts, coupled with depletion of Tregs, immunosuppressive neutrophils, myofibroblasts, and angiogenic endothelial cells.