WD-3 improves anti-PD-L1 therapy by remodeling the tumor immune microenvironment through gut microbiota

BACKGROUND: Gastric cancer (GC) ranks as the fifth most prevalent malignancy globally. Emerging evidence implicates gut microbiome as a key modulator of anti-tumor immunity and immunotherapy response. Traditional Chinese Medicine (TCM) presents a promising yet underexplored avenue for microbiome modulation. METHODS: 16S rDNA sequencing of fecal samples was used to detect changes of gut microbiota in advanced GC patients. GC models were established in huPBMC-NOG-dKO mice after fecal microbiota transplantation (FMT) to investigate the potential synergy between Number 3 Prescription (WD-3) and anti-PD-L1 monoclonal antibody (mAb) in treatment of non-responders. RESULTS: In this study, WD-3 combined with αPD-L1 showed additive benefit after the FMT of non-responders in the humanized mouse model model. WD-3 combination therapy correlated with reduced proportion of Treg cell infiltration in tumors. WD-3 combination was also associated with increased species richness and improved gut microbiota community structure compared to αPD-L1 alone, with increased relative abundances of Enterobacteriaceae and Lachnospiraceae. CONCLUSION: Our data provide correlative evidence that WD-3 supplementation combined with αPD-L1 treatment may attenuate GC progress in the FMT mouse model, indicating association with the modulation of gut microbiota. These findings aim to provide treatment strategies for the clinical treatment of advanced GC.