Glucose restriction induced by intermittent fasting promotes alternative metabolic fluxes leading to memory CD8⁺ T cell development

Dietary restrictions are increasingly recognized as modulators of immune cell function. However, how they shape CD8⁺ T cell fate decisions remains incompletely understood. Here, we investigated the impact of intermittent fasting (IF) on differentiation of heterogeneous effector T cell subsets and the formation of a long-lived homeostatic memory pool. We found that IF skewed CD8⁺ T cell differentiation toward memory precursor effector cells (MPECs) and enhanced the central memory CD8⁺ T cell development and functions. Mechanistically, glucose restriction induced by IF promotes alternative metabolic fluxes leading to fatty acid oxidation. This metabolic shift enhanced mitochondrial fitness and supported MPEC differentiation via metabolic-epigenetic cross-talk, culminating in durable and functionally robust memory CD8⁺ T cell responses. Applying this strategy in adoptive transfer therapy, intratumoral defects could be circumvented by imprinting a memory phenotype under IF-mimicking conditions, resulting in improved and long-lasting antitumor activity. Collectively, these findings underscore the importance of IF in orchestrating metabolic-epigenetic cross-talk to enhance memory formation and antitumor immunity.