Myeloid-derived suppressor cells deficient in cholesterol biosynthesis promote tumor immune evasion

Cancer immunotherapy targeting myeloid-derived suppressor cells (MDSCs) is one of the most promising anti-cancer strategies. Metabolic reprogramming is vital for MDSC activation, however, the regulatory mechanisms of cholesterol metabolic reprogramming in MDSCs remains largely unexplored. Using the receptor-interacting protein kinase 3 (RIPK3)-deficient MDSC model, a previously established tumor-infiltrating MDSC-like model, we found that the cholesterol accumulation was significantly decreased in these cells. Moreover, the phos-phorylated AKT-mTORC1 signaling was reduced, and downstream SREBP2-HMGCR-mediated cholesterol syn-thesis was blunted. Interestingly, cholesterol deficiency profoundly elevated the immunosuppressive activity of MDSCs. Mechanistically, cholesterol elimination induced nuclear accumulation of LXR beta, thereby promoting LXR beta-RXR alpha heterodimer binding of a novel composite element in the promoter of Arg1. Furthermore, itraco-nazole enhanced the immunosuppressive activity of MDSCs to boost tumor growth by suppressing the RIPK3-AKT-mTORC1 pathway and impeding cholesterol synthesis. Our findings demonstrate that RIPK3 deficiency leads to cholesterol abrogation in MDSCs, which facilitates tumor-infiltrating MDSC activation, and highlight the therapeutic potential of targeting cholesterol synthesis to overcome tumor immune evasion.

Automated summary

Cancer immunotherapy targeting myeloid-derived suppressor cells (MDSCs) is a promising anti-cancer strategy. This study explored the regulatory mechanisms of cholesterol metabolic reprogramming in MDSCs and found that cholesterol deficiency increased the immunosuppressive activity of MDSCs. Mechanistically, cholesterol elimination induced nuclear accumulation of LXR beta and enhanced the binding of LXR beta-RXR alpha on Arg1 promoter. Furthermore, itraconazole improved MDSC immunosuppressive activity and promoted tumor growth by inhibiting the RIPK3-AKT-mTORC1 pathway and impeding cholesterol synthesis.