Figure 5.

Indole derivatives derived from bacteria serve as facilitators for augmenting the efficacy of chemotherapy and ICI in cancer. (A) Trp metabolites originating from the gut microbiome accelerate the chemotherapy response in pancreatic cancer. Intestinal bacteria generate IAA from absorbed dietary Trp. IAA is transported to PDAC through the bloodstream, where it may undergo oxidation to produce toxic molecules (IAAp) facilitated by myeloperoxidase (MPO) and cytotoxic anticancer drugs such as 5-fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) within intratumoural neutrophils. Subsequently, IAAp and FOLFIRINOX jointly contribute to the downregulation of GPX3/7, enzymes responsible for degrading ROS, leading to the accumulation of ROS within cancer cells. Ultimately, elevated ROS levels inhibit the autophagy pathway, a crucial process in cancer cell proliferation. (B) L. reuteri translocates to, colonizes, and persists within melanoma, where, through the release of its dietary tryptophan catabolite I3A, it locally enhances the generation of IFN-γ-producing CD8⁺ T cells, thereby augmenting the efficacy of ICI. Furthermore, I3A was found to be both necessary and sufficient to stimulate antitumour immunity, and the loss of AHR signaling within CD8⁺  T cells abolished antitumour effects.