Targeting metabolic reprogramming to enhance adoptive immunotherapy: emerging mechanisms and translational perspectives

BACKGROUND: Adoptive cell therapy (ACT) has achieved breakthrough advances in the treatment of malignancies, demonstrating particularly remarkable efficacy in hematologic cancers. However, the therapeutic efficacy of ACT remains limited by multiple factors, including low tumor antigen expression, the limited in vivo persistence of infused immune cells, and the immunosuppressive characteristics of the tumor microenvironment (TME). Meanwhile, metabolic reprogramming, a hallmark of cancer, plays a pivotal role in immune cells by directly regulating their differentiation, functional states, and long-term survival. Metabolic stress within the TME, including hypoxia, nutrient competition, and accumulation of metabolic byproducts, reshapes the metabolic states of T cells, natural killer (NK) cells, and macrophages, thereby profoundly affecting their activation, effector functions, and in vivo persistence. Consequently, a systematic understanding of how metabolic reprogramming regulates immune cell function is crucial for overcoming the current therapeutic limitations of ACT. MAIN BODY: This review systematically summarizes the metabolic constraints faced by immune effector cells in ACT and the strategies to modulate them, with a particular focus on the impact of glycolysis, lipid metabolism, amino acid homeostasis, and mitochondrial function on immune cell differentiation, effector functions, and in vivo persistence. In addition, it provides a comprehensive discussion of potential approaches to target metabolic reprogramming through pharmacological interventions and genetic engineering, aiming to overcome the metabolic limitations imposed by the TME and enhance the antitumor efficacy of ACT. CONCLUSION: While merely enhancing glycolysis can transiently increase the cytotoxic activity of immune effector cells, it often leads to metabolic exhaustion and reduced persistence. In contrast, optimizing mitochondrial function, boosting oxidative phosphorylation and fatty acid oxidation, and maintaining metabolic flexibility are more conducive to promoting memory-like phenotypes and supporting long-term survival and functional maintenance of immune cells in vivo. Future studies should integrate genetic engineering with metabolic interventions to optimize the antitumor activity of ACT in solid tumors and complex tumor microenvironments, thereby providing a theoretical foundation and translational pathway for the development of next-generation, safe and efficacious ACT therapies.