Epigenetic regulation of immune checkpoint signaling by microbial metabolites: mechanisms, therapeutic potential, and future perspectives.

The gut microbiome has emerged as an important regulator of host immunity through the production of diverse bioactive metabolites. The gut microbiome has emerged as an important regulator of host immunity through the production of diverse bioactive metabolites. Microbiota-derived metabolites influence immune cell function and contribute to the maintenance of immune homeostasis, serving as key molecular mediators of host-microbiota communication. Importantly, while evidence is emerging that these metabolites affect immune checkpoint signaling, less is known about the molecular mechanisms behind these interactions. Recent research demonstrated that SCFAs, secondary bile acids, indoles derived from tryptophan, inosine, polyamines and other microbial metabolites affect the immune checkpoints through epigenetics, metabolism, receptor signaling, and intracellular pathway modulation. These interactions affect the expression and functioning of key immune checkpoint molecules such as PD-1, PD-L1, CTLA-4, LAG-3, TIGIT, TIM-3 and VISTA. In this review, we summarize current knowledge regarding the Metabolite-Immune Checkpoint Axis, stressing the role of metabolites derived from microbiota in the regulation of immune checkpoints. We elaborate on the molecular mechanisms of these interactions and their significance in the context of cancer, autoimmune disorders, chronic inflammatory disorders, and infectious diseases. We also provide insights regarding the developing therapeutic strategies based on microbiome-modulated therapy. Finally, we highlight key knowledge gaps and future research directions required for the clinical translation of microbiome-based personalized therapies.