A novel microbial-derived metabolite counteracts exhaustion programming in CD8 T cells 2260531

Abstract Introduction Exhaustion of CD8 T cells during cancer or chronic infections remains a significant barrier to T cell immunotherapies. Recent studies showed that distinct epigenetic changes drive exhaustion by silencing effector and memory-related genes, thereby establishing the dysfunctional state of exhausted T cells (TEX). Thus, targeting epigenetic regulation of exhaustion is crucial for restoring TEX cell function. Short-chain fatty acids (SCFAs) are emerging as key mediators linking cellular metabolism to gene regulation. Notably, certain SCFAs naturally produced by human microbiota have been shown to modulate host immune responses through epigenetic mechanisms. Methods To investigate their effects on TEX cell epigenetic programming, we utilized innovative in vitro T cell exhaustion models that generate stable terminal dysfunction in both human and mouse CD8 T cells. By inducing a state of exhaustion that recapitulates key molecular and functional features observed in cancer and chronic infections, these models enabled us to assess how SCFA treatment affects T cell function and memory-associated stemness features. Results We discovered that a specific microbial SCFA triggered a significant recovery of polyfunctionality and memory programs within both human and mouse dysfunctional T cells. SCFA-treated TEX cells exhibited renewed effector capabilities, such as enhanced cytokine production, degranulation, and tumor-killing activity. The enhanced effector functions persisted even following termination of SCFA treatment, suggesting stable reprogramming of TEX cells. Conclusion These findings identify a novel microbial SCFA as a potential metabolic-epigenetic regulator, capable of reactivating effector programs in TEX cells while blocking terminal exhaustion. These results provide insights into developing new therapeutic approaches to reprogram TEX cells and enhance the efficacy of T cell immunotherapy. Funding Source n/a Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)