Reprogramming Glutamine Metabolism of Dendritic Cells Boosts Lymph Nodes Migration and Tumor Immunotherapy

Abstract Type 1 conventional dendritic cells (cDC1s) are key antigen‐presenting cells that efficiently activate CD8 + T cells, driving strong anti‐tumor immunity. cDC1s migration to the lymph node is a pivotal component. Previous studies often focused on enhancing dendritic cells (DCs) migration via the CC chemokine receptor (CCR) 7 – CC chemokine ligand (CCL) 19/21 pathway, while simultaneously increasing tumor cell metastasis. In this study, a new strategy is provided to accelerate DCs’ movement out of tumor by reprograming their glutamine metabolism without causing metastasis of tumor cells. cDC1s‐targeting peptide‐modified liposomes are used to precisely deliver a glutamine uptake receptor SLC38A2 messenger RNA (mRNA) to cDC1s, which increased their need for glutamine and strengthens their trophic gradient tendency toward the lymph nodes. In addition, cDC1s with SLC38A2 overexpression showed higher levels of maturation and activation. In vivo experiments demonstrate significant activation of CD8 + T cells and inhibition of tumor growth when systematic administration of such nanomedicine in mouse models of colorectal carcinoma. The results demonstrate a new insight into regulating DCs behavior, especially lymph node migration, for enhancing anti‐tumor immunity.