*2.4. Gut Microbiota and TME*

The gut microbiota shapes the immune system in the early years of life, and alterations in the gut microbiota later in life have a significant impact on numerous immune system functions [50]. The relationship between the gut microbiota and the host immune system increases the likelihood that the TME will interact with larger systemic microbial–immune networks, which serves as a reminder that the gut microbiota is increasingly acting as a crucial TME regulator [51–55]. The intestinal bacterium *B. pseudolongum* produces the metabolite inosine, which, by acting on the adenosine A2A receptor on T cells, significantly promotes Th1 cell differentiation in the presence of exogenous IFN-γ and improves the therapeutic response to immune checkpoint inhibitor (ICI) therapy, including anti-CTLA-4 and anti-PD-L1 [56]. A study showed that some gut bacteria, including *Bacteroides* and *Ruminococcaceae*, can contribute to the development of hepatocellular carcinoma by escalating hepatocyte inflammation, building up toxic substances, and causing liver steatosis [57]. According to the "holobiont" idea, it was recently proposed that the gut microbiome influences the "TME", which in turn affects tumor growth [52,58]. Ohtani et al. reported that the intestinal microbiota of obese individuals increases the amount of deoxycholic acid in the blood, which in turn promotes liver carcinogenesis by causing hepatic stellate cells to exhibit a senescence-associated secretory phenotype [59,60]. Altogether, these findings strongly suggest the crucial role that gut dysbiosis plays in the influence on TME microbiota and the efficacy of cancer therapeutic drugs/modes.
