Bacterial tryptophan metabolites in cancer and atherosclerosis: insights for a role in immune checkpoint inhibition

The gut microbiota plays a pivotal role in human health, partly through the production of bioactive metabolites from dietary tryptophan. These indole derivatives have emerged as key modulators of immune function, inflammation, and metabolic health and have been linked to various diseases. In the context of cancer, indole derivatives are increasingly being studied as promising modulators of immune checkpoint inhibitor (ICI) therapy, with accumulating evidence indicating potential for various derivatives to enhance therapeutic efficacy. ICI therapy is associated with various immune-related adverse events, including accelerated progression of atherosclerotic cardiovascular disease. Given their immunomodulatory properties, there is a growing interest in the usage of indole metabolites to mitigate these cardiovascular complications. This mini-review summarizes current knowledge on the roles of microbiota-derived indoles in cancer, ICI therapy, and atherosclerosis. Though direct evidence linking bacterial tryptophan-derived metabolites to ICI-associated atherosclerosis is currently lacking, accumulating evidence indicates that indole derivatives regulate pathways involved in both anti-tumor immunity and atherosclerosis. Advancing our understanding of how the microbiome and its metabolites influence both cancer and cardiovascular disease will be crucial for developing personalized, metabolite-based strategies to improve outcomes in patients undergoing ICI therapy.