Gut microbiota – indole-3-acetic acid axis in cancer: dual functions, mechanistic insights, and therapeutic potential

Indole-3-acetic acid (IAA), a gut microbial metabolite produced from dietary tryptophan, has a dual role in cancer, either promoting or suppressing tumor growth depending on its concentration and the cancer context. IAA can boost chemotherapy effectiveness by increasing reactive oxygen species (ROS), disrupting autophagy, and damaging cancer cells. It also activates the aryl hydrocarbon receptor (AhR), which promotes an immunosuppressive tumor-associated macrophage (TAM) phenotype and reduces T-cell activity, aiding in tumor growth. Additionally, IAA engages the Toll-like receptor 4 (TLR4), activating the c-Jun N-terminal kinase (JNK) signaling pathway to regulate cell growth and limit tumor proliferation. On the other hand, IAA offers protective effects by strengthening the intestinal barrier, reducing inflammation, and promoting Treg cell activity. IAA, recognized as a uremic toxin, can accumulate when clearance is impaired, leading to increased oxidative stress and inflammation that may further aggravate kidney disease and promote cancer development. This review highlights how gut microbes shape IAA levels in cancer patients, which vary widely between individuals. Unlike other tryptophan metabolites, IAA has a unique dual role in cancer, both promoting and suppressing tumors depending on the context. Understanding how microbes and the host environment influence IAA may open new paths for targeted cancer therapies.