Creatine uptake promotes dendritic cell activation and enhances antitumor immunity

Dendritic cells (DCs) are central regulators of antitumor T cell immunity and are highly sensitive to metabolic cues. However, the therapeutic potential of targeting DC metabolism remains underexplored. Here, we report upregulation of the creatine transporter (CrT; Slc6a8) in intratumoral DCs, which facilitates the cellular uptake of creatine, an energy-storage metabolite. DCs from CrT knockout mice exhibited impaired activation and reduced ability to elicit antigen-specific CD8 T cell responses. Conversely, creatine supplementation enhanced mouse DC activation in vitro and in vivo, and suppressed tumor growth in a syngeneic melanoma model. Notably, creatine uptake similarly boosted the activation and immunostimulatory function of human monocyte-derived DCs. Mechanistically, CrT promotes DC activation by preserving intracellular ATP levels and enhancing energy-dependent inflammatory signaling pathways. Together, these findings uncover a previously unrecognized role for creatine metabolism in regulating DC function and support the use of creatine supplementation as a strategy to augment DC-based cancer immunotherapy.