The TRIM27/STING Axis Mediates Schisandrin B-Induced Inhibition of Myeloid-Derived Suppressor Cells Accumulation to Potentiate Anti-PD-1 Immunotherapy in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is characterized by a highly immunosuppressive microenvironment, which contributes to its unfavorable clinical outcomes. Myeloid-derived suppressor cells (MDSCs) play a crucial role in this process. Schisandrin B (SchB) shows anti-tumor potential, but its mechanism in suppressing MDSCs remains unclear. This study investigates how SchB inhibits MDSCs accumulation and enhances anti-PD-1 therapy efficacy in HCC.SchB's efficacy and mechanism were investigated both in vitro and in vivo. In vitro, MTT, wound healing, EdU, colony formation, flow cytometry, ELISA, western blot, immunofluorescence, Co-IP, molecular dynamics (MD), and CETSA assays were employed to evaluate the therapeutic effects and mechanistic action of SchB on HCC. In vivo, a mouse HCC xenograft model was used to evaluate whether SchB could enhance the anti-tumor effect of PD-1 mAb and the potential mechanism.Mechanistically, SchB suppressed TRIM27 expression, disrupted the interaction between TRIM27 and STING, and enhanced STING/TBK1/IRF3 signaling, thereby suppressing the secretion of IL-6 and GM-CSF as well as the accumulation of MDSCs. SchB could directly bind to TRIM27 and downregulate its expression, thereby enhancing STING protein stability. In vivo, SchB effectively reduced MDSCs accumulation while promoting T cell recruitment, thereby augmenting the antitumor efficacy of PD-1 mAb therapy.SchB up-regulates STING by suppressing TRIM27, inhibits IL-6/GM-CSF secretion, and reduces MDSCs accumulation, indicating that SchB has the potential to be a promising candidate for PD-1 inhibitor therapy in HCC.