Clarifying and overcoming CAR-T cell exhaustion: glucose metabolic mechanisms and intervention strategies

Chimeric antigen receptor (CAR)-T cell therapy has emerged as a transformative treatment for hematologic malignancies; however, its long-term efficacy is severely limited by poor cell persistence. CAR-T cell exhaustion has been recognized as a core factor limiting its persistence. Although multiple factors contribute to CAR-T cell exhaustion, recent studies have highlighted metabolic reprogramming as a particularly important and therapeutically actionable contributor. This review focuses on the critical role of glucose metabolism in driving cellular exhaustion, with particular emphasis on how glucose metabolic disorders and mitochondrial dysfunction act as key contributors. Furthermore, we summarize four principal intervention strategies, including in vitro metabolic pretreatment, in vivo counteraction of tumor microenvironment (TME) metabolic stress, metabolism-related gene engineering, and optimization of CAR structures. Collectively, this review provides a framework linking glucose metabolism-driven exhaustion to actionable metabolic interventions, thereby offering potential directions for mitigating CAR-T cell exhaustion. Current clinical translation challenges include balancing persistence with effector function, controlling toxicity, and addressing metabolic heterogeneity. Future research should prioritize these bottlenecks by exploring high-potential strategies such as pharmacological interventions and CAR structural modifications, as well as developing personalized regimens tailored to metabolic profiles to enhance long-term efficacy.