Myeloid-derived suppressor cells in the tumor microenvironment reduce uncoupling protein 1 expression to boost immunosuppressive activity

Uncoupling protein 1 (UCP1) is located at the inner membrane of mitochondria and mediates nonshivering thermogenesis. Its abnormal expression is associated with metabolic diseases, cancer, and acute kidney injury. Myeloid-derived suppressor cells (MDSCs) with immunosuppressive activity accumulate in the tumor microenvironment (TME). Here, decreased UCP1 expression in MDSCs was observed in the peripheral blood of patients with colorectal cancer and transplanted mouse tumors. Aggravated tumor progression was observed in UCP1-knockout mice and conditional knockout mice (UCP1fl/fl-S100A8cre). The number of G-MDSCs and M-MDSCs increased in the transplanted tumor tissues from UCP1-deficient mice compared with those from wild-type mice. The tumor-promoting effect disappeared when the tumor-bearing mice were depleted of MDSCs by the α-DR5 administration. Adoptive transfer of tumor-derived MDSCs sharply promoted the tumor growth in vivo. Furthermore, these tumor-derived MDSCs enhanced the proliferation, reduced death, inhibited IFN-γ production of CD4+ and CD8+T cells, and induced Treg cells ex vivo. In conclusion, MDSCs in the TME alter the metabolic pattern by decreasing UCP1 expression to enhance immunosuppressive activity for tumor escape. •UCP1 drastically decreased in MDSCs from colorectal cancer patients' blood and mouse tumors.•Loss of UCP1 promoted MDSCs proliferation and immunosuppressive activity in the tumor microenvironment.•Reduced UCP1 led to the metabolic reprogramming of MDSCs, enhancing proliferation and reducing cell death.