Functional and metabolic dysbiosis of the gut microbiome in the tumoral immune microenvironment of hepatocellular carcinoma.

With its asymptomatic and heterogeneous nature, hepatocellular carcinoma (HCC) ranks as one of the most fatal malignancies globally, contributing to a deteriorating five-year overall survival. The gut microbiome, as the resident microorganism of the digestive tract, has been linked to a variety of hepatic disorders based on the internal "gut-liver" axis, accompanied by alterations in microbial components and derived metabolites. We found that patients with HCC had a greater abundance of Streptococcus salivarius (S. salivarius) and lithocholic acid (LCA), but its role in the tumor immune microenvironment remains elusive. Methodologically, we conducted 16S rRNA, 5R 16S rRNA sequencing and metabolomic analysis to discern the impact of S. salivarius in C-Myc/NRas-driven HCC mouse model and RNA-sequencing (RNA-seq) was performed to clarify the particular pathophysiological mechanism. In addition, the effect of S. salivarius on the efficacy of Anti-PD1 immunotherapy was evaluated as well. Mechanistically, S. salivarius was demonstrated to impede the cGAS/STING axis, consequently dampening the anti-tumor immune response by restricting the CD8+ T cell trafficking to tumor microenvironment (TME) and triggering the immunosuppressive factor PD-1. Meanwhile, the integrative analysis indicated that the generated LCA facilitated the translocation of S. salivarius towards tumor site and activated the tumor-associated macrophages (TAMs), which altogether reshaped the immune TME in HCC. Our findings revealed perturbed microbial and metabolic features in the pathogenesis of HCC and offered a motivation for considering potential interventions during patient treatment.