Fig. 4

Effects of glutamine metabolism inhibitors on immune response. Glutamine antimetabolites L-DON and JHU-083 can inhibit glutamine metabolism, glycolysis, and OXPHOS in tumor cells, and comprehensively disintegrate the energy metabolism of tumors (①). Glutamine antimetabolites directly modulate the metabolism of CD8⁺CTLs to promote a long-lasting, activated, memory-like phenotype; enhance cytokine production; and inhibit exhaustion and apoptosis (②). Glutamine antimetabolites inhibit the generation and recruitment of MDSCs and induce the differentiation of MDSCs and TAMs into pro-inflammatory TAMs by suppressing the secretion of CSF3 (③). Glutamine antimetabolites inhibit the expression of IDO in tumor and myeloid derived cells; reduce the levels of kynurenine; and enhance anti-tumor immune response (④). Glutamine antimetabolites inhibit the HBP metabolic pathway; decrease the levels of hyaluronan; change the mechanical properties of the ECM; improve the immunosuppressive TME and enhance the anti-tumor immune response (⑤). Glutamine uptake inhibitor V-9302 has distinct effects on the differentiation of T cell subsets, favoring CD4⁺Th1 and CD8⁺CTL but reducing the levels of Treg cells (⑥, ⑧). Glutaminase inhibitor CB-839 enhances the activation of CD4 ⁺ Th1 and CD8⁺ CTL but suppress the differentiation of CD4⁺Th17 cells (⑦, ⑧)