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

## TL;DR

T26 is a new drug that combats colorectal cancer by blocking glutamine metabolism and boosting immune responses, improving treatment effectiveness.

## Contribution

T26 is a novel bifunctional prodrug that simultaneously targets glutamine metabolism and activates the STING pathway in dendritic cells.

## Key findings

- T26 restores dendritic cell maturation and CD8⁺ T cell activation in murine CRC models.
- T26 reprograms tumor-derived extracellular vesicles to enhance antigen presentation and immune stimulation.
- T26 synergizes with chemotherapy, immune checkpoint blockade, and anti-angiogenic therapy to improve tumor control.

## 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.

T26 is an immunometabolic prodrug that modulates colorectal cancer cells. It blocks glutamine metabolism and enhances STING signaling, which promotes the release of reprogrammed extracellular vesicles. These vesicles drive dendritic cell maturation and CD8⁺ T cell activation, thereby strengthening antitumor immunity and improving the effectiveness of existing therapies.