Alpha-ketoglutarate Potentiates IL-1β Production and Suppressive Mechanisms of Myeloid-Derived Suppressor Cells by Altering Redox Metabolism and Inducing Autophagy.

Alpha-ketoglutarate (αKG) has shown promise in cancer immunotherapy due to its profound impact on cancer cell metabolism and gene expression. However, its effects on myeloid-derived suppressor cells (MDSCs), critical immunosuppressive components of the tumour microenvironment, remain poorly understood. Using a model of GM-CSF/IL-6-induced monocyte-derived (mo)MDSCs we found that non-toxic doses of non-esterified αKG expanded CD14+HLA-DR-/low moMDSCs, unlike esterified dimethyl-αKG. The αKG-moMDSCs displayed an enhanced suppressive phenotype, upregulated ILT-4 and IL-10, and showed an increased capacity to suppress Th1 cells. However, αKG-moMDSCs exhibited a heightened IL-1β production upon LPS stimulation, promoting Th17 cell expansion. This pro-inflammatory effect was consistent with oxoglutarate receptor (OXGR1)-dependent ROS increase, reduced Erk1/2 and Akt phosphorylation, reduced NRF-2 nuclear translocation and altered oxidative phosphorylation, as it could be mitigated by OXGR1-specific small interfering (si)RNAs delivered via lipid nanoparticles. Notably, the enhanced capacity of αKG-moMDSCs to suppress T cell proliferation and induce conventional FoxP3+ regulatory T cells was independent of OXGR1, relying instead on Atg5-mediated increase in autophagy flux and IL-10 production. Atg5 was dispensable for ILT-4 upregulation, but still essential for the induction of FoxP3- type 1 and type 2 regulatory T (Tr1 and Tr2) cells, as well as OXGR1/ROS-mediated Th17 induction. Therefore, non-esterified αKG may promote moMDSC-mediated chronic inflammation and T cell dysregulation, potentially compromising its therapeutic efficacy in cancer immunotherapy.