Triptolide impacts CSF1R expression and reprograms the suppressive function of myeloid-derived suppressor cells via targeting the ER stress pathway.

Triptolide (TPT) is a natural compound in herbal remedies with anti-inflammatory and anti-tumor properties. The study aimed to investigate the therapeutic effect of triptolide treatment on Myeloid-derived suppressor cells (MDSCs) in Hepatocellular Carcinoma (HCC). Single-cell transcriptomic profiling of liver tumor biopsies identified (Colony-Stimulating Factor 1 Receptor) CSF1R MDSCs as a distinct MDSCs lineage in HCC patients, which exhibited a positive correlation with the severity of HCC. Flow cytometric analysis confirmed CSF1R MDSCs were enriched in the peripheral blood and tumor tissue of HCC patients. Elevated CSF1R expression were highly expressed on the polymorphonuclear-MDSCs (PMN-MDSCs) subset specifically. Notably, PERK-mediated endoplasmic reticulum (ER) stress activation contributed to CSF1R induction, as evidenced by inhibiting the activities of PERK, but not IRE1α or ATF6, successfully attenuated the frequency of CSF1R MDSCs. Moreover, TPT dose-dependently diminished MDSCs and CSF1R MDSCs frequencies, alongside with alleviating the immunosuppressive capability on T cell proliferation. Further investigation revealed TPT treatment suppressed phosphorylation of PERK, as well as the protein levels of ATF4 and C/EBPβ. Our results underscore the role of ER stress-induced CSF1R expression in driving HCC disease progression by promoting the immunosuppressive effects of MDSCs, and identify CSF1R as a promising immunosuppressive target of TPT in HCC therapy.