Immunometabolic Rewiring of Dendritic Cells to Overcome Glutamine‐Driven Immune Suppression in Colorectal Cancer

Abstract The immunosuppressive tumor microenvironment imposes significant metabolic constraints that impair dendritic cell (DC) maturation and antigen presentation, ultimately undermining antitumor immunity. In colorectal cancer (CRC), elevated glutamine uptake by tumor cells depletes extracellular glutamine, thereby limiting DC functionality and disrupting T cell priming. While glutamine antagonists such as JHU083 inhibit tumor metabolism, they are insufficient to fully restore DC activity. Here, the development of T26, a bifunctional immunometabolic prodrug that links JHU083 with the STING agonist MSA‐2 via a cleavable amide bond, is reported, enabling synchronized intratumoral release and dual targeting of glutamine metabolism and innate immune activation. In murine CRC models, T26 restores DC maturation, promotes CD8⁺ T cell activation, and reprograms tumor cell‐derived extracellular vesicles to enhance antigen presentation and immune stimulation. Importantly, T26 significantly inhibits the growth and proliferation of CRC patient‐derived organoids, underscoring its translational potential in human CRC. Notably, T26 also demonstrates strong synergy with chemotherapy, immune checkpoint blockade, and anti‐angiogenic therapy, significantly improving tumor control without inducing systemic toxicity. These findings position T26 as a mechanistically integrated and translationally promising strategy to overcome glutamine‐driven immune suppression and enhance immunotherapy efficacy in CRC and other metabolically dysregulated malignancies.