Cholesterol 25-hydroxylase enhances immunosuppressive function of MDSCs in colorectal cancer

Myeloid-derived suppressor cells (MDSCs) represent a substantial population of immunosuppressive cells within the tumor microenvironment (TME) of colorectal cancer. Previous studies have established a strong association between the immunosuppressive activity of MDSCs and the reprogramming of cholesterol metabolism; however, the underlying mechanisms remain to be fully elucidated. In this study, we identified that cholesterol 25-hydroxylase (CH25H) and its metabolite, 25-hydroxycholesterol (25HC), are significantly elevated in MDSCs associated with colorectal cancer. The knockdown of CH25H led to a decrease in the immunosuppressive capabilities of MDSCs, which was linked to the inhibition of Arginase-1 (ARG1) expression; conversely, the administration of 25HC counteracted this effect. Mechanistically, 25HC was shown to downregulate the Cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) (cGAS-STING) pathway and its downstream signaling component, TANK binding kinase 1(TBK1). Upon phosphorylation and activation, TBK1 inhibited ARG1 production. In summary, our findings indicate that CH25H-mediated accumulation of 25HC enhances the immunosuppressive function of MDSCs and promotes immune evasion in colorectal cancer by suppressing the STING-TBK1- receptor-interacting protein kinase 3(RIPK3) signaling axis. This study uncovers a novel signaling pathway involving CH25H and STING in tumor immunomodulation and suggests that targeting cholesterol metabolism may provide a promising therapeutic strategy for colorectal cancer immunotherapy.