Engineered DCs reprogram the TME to unleash immunotherapy and CAR-T efficacy in lung cancer models

Resistance to immune checkpoint blockade (ICB) remains a major barrier in non-small cell lung cancer (NSCLC), where defective antigen presentation, myeloid-cell dominance, and immune exclusion limit anti-tumor immunity. In this study, I 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;Tp53-/- ung 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 immunostimulatory fibroblasts, coupled with depletion of Tregs, immunosuppressive neutrophils, myofibroblasts, and angiogenic endothelial cells. IFNγ neutralization abrogated the therapeutic response, underscoring its central role in orchestrating cross-compartmental reprogramming. IRF1 was concordantly expressed across epithelial, immune, and stromal compartments in human cancer and correlated with ICB response, highlighting the relevance of DCP-induced inflammatory programs in cancer control.