Bacteria‐Trained, MnO 2 ‐Armored Dendritic Cells for Immunotherapy

ABSTRACT Precise control over the phenotypic state of immune cells is critical for overcoming the limitations of on‐target off‐tumor toxicity and inefficient tumor infiltration in cell‐based cancer immunotherapy. Here, we developed an engineered DC platform—trained with inactivated bacteria and armored with MnO 2 nanoparticles (designated MnArmL‐trDCs)—endowed with immune reconfigurability and mechano‐transformable characteristics to boost tumor penetration and remodel immune microenvironment. In circulation, the MnO 2 armor enforces a stiff mechanical state and globally masks surface immunological ligands (such as CD80, CD86, MHC‐II, and CCR7), rendering the DCs biologically silent and resistant to premature immune recognition or hepatic clearance. These engineered cells integrate selectively into lesion sites, enabling restoration of the deformability of dendritic cells and targeted intratumoral immune activation triggered by local pH and hydrogen peroxide. This transformation enables deep tumor penetration, robust activation of TLR, NLR, and cGAS‐STING pathways, and efficient trafficking to tumor‐draining lymph nodes. In vivo, MnArmL‐trDCs induce a pro‐inflammatory immune landscape, promote cytotoxic lymphocyte infiltration, reverse immunosuppression, and synergize with anti‐PD‐1 therapy to achieve sustained tumor regression. This nano‐engineering cell armor‐based strategy could also be possibly expanded to different cell types in other types of immunotherapies.