Inhibition of Glutamine Metabolism Attenuates Tumor Progression Through Remodeling of the Macrophage Immune Microenvironment.

Targeting glutamine metabolism has emerged as a promising strategy in cancer therapy. To attain clinical utility, a number of challenges must be overcome, including in vivo anti-tumor activity, pharmacological toxicity, and clinical safety. Aside from glutamine-addicted tumor cells, immune cells may also need glutamine to sustain physiological activities; thus, the current work used two immunological-intact murine cancer models to assess the effects of glutamine antagonists on tumor cells and the immune milieu. To minimize potential off-target effects, we developed a glutamine antagonist prodrug, JHU083, which is bioactivated selectively in cancer tissues. In both murine tumor models, we observed a significant anti-tumor effect, resulting in reduced tumor burden and impeded tumor progression. Single-cell RNA sequencing of tumor tissues demonstrated that JHU083 significantly hampered the immunosuppressive M2-like macrophages but not the pro-inflammatory M1-like macrophages. Expression of Myc- and hypoxia-regulated genes were also inhibited by JHU083. Ex vivo bone marrow-derived macrophage cultures further confirmed that M2 macrophages were more sensitive to glutamine antagonist than M1 macrophages. Together, our findings indicate that JHU083 exerted its anti-tumor activity not only through direct targeting of glutamine-addicted cancer cells but also by shifting the M1/M2 macrophage landscape in favor of an immune-stimulatory microenvironment.