Microbiota-derived indole derivatives as anticancer agents: mechanistic insights and major perspectives

Abstract

Cancer remains a major global health challenge, and emerging research highlights the role of the gut microbiota in cancer development. This complex microbial community supports digestion, immunity, and even mental well-being, adapting to lifestyle factors like diet and exercise. One key function is the breakdown of tryptophan (Trp) into indole. Studies have linked these compounds to cancer, inflammatory conditions, and brain disorders. This review compiles evidence showing that indole derivatives produced by gut bacteria could serve as potential anticancer agents by targeting specific biochemical pathways. Mechanistically, these metabolites inhibit IDO1, lower kynurenine levels, decrease regulatory T cells, and increase CD8+ T cell responses. They also activate tumor-suppressive signaling pathways such as the aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR), and nuclear factor erythroid 2-related factor 2 (NRF2), while regulating reactive oxygen species (ROS). In addition, some indole derivatives trigger interleukin-12 (IL-12)-mediated T cell activation, leading to metabolic stress in cancer cells by downregulating UHRF1 and activating AMP-activated protein kinase (AMPK), thereby depleting ATP and causing cell death. Relevant literature was identified from PubMed, Google Scholar, and Scopus up to January 2026. Collectively, understanding this link could support development of personalized diets and microbiota-based cancer therapies.