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.