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  • Epigenetic and Metabolic Networks Shaping CAR-T Cell Exhaustion and Memory

  • Seyed Mostafa Rahimi,1 Fatemeh Arab Mirrahmani,2 Mohsen Najafi,3,*
    1. Cellular and Molecular Biology Research Center, Health Institute, Babol University of Medical Sciences
    2. Department of Human Genetics, Negin Genetics & Pathobiology Laboratory, Negin Medical Complex
    3. Medical Genomics Research Center, Tehran Medical Sciences Islamic Azad University


  • Introduction: Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment of haematological malignancies; however, durable clinical responses remain limited in a substantial proportion of patients due to multiple factors, including inadequate persistence, progressive acquisition of dysfunctional cellular states, antigen escape, tumour microenvironmental constraints, and manufacturing-related variability. Emerging evidence indicates that CAR-T cell dysfunction involves multiple dynamic differentiation trajectories, including exhaustion-associated states, shaped by reciprocal interactions among epigenetic regulation, cellular metabolism, signalling networks, and the tumour microenvironment.
  • Methods: This narrative Review examines how DNA methylation, histone modification, enhancer regulation, mitochondrial and redox metabolism, and metabolite-dependent chromatin regulation collectively shape trajectories among memory-associated, progenitor-exhausted, transitory or effector-like exhausted, and terminally exhausted CAR-T cell states.
  • Results: We discuss emerging therapeutic approaches, including pharmacological epigenetic modulation, sequence-based genome editing, programmable transcriptional and epigenome engineering approaches, and metabolic conditioning strategies, while considering their limitations in safety, durability, heterogeneity, and clinical translation. We propose an integrated dynamical-systems framework in which advanced exhaustion-associated configurations may behave as attractor-like states emerging from context-dependent and reinforcing epigenetic, metabolic, and signalling feedback circuits.
  • Conclusion: Understanding and manipulating these regulatory networks may enable the development of next-generation CAR-T therapies with enhanced persistence, functional stability, and improved applicability across haematological malignancies and selected preclinical solid-tumour settings.
  • Keywords: Chimeric Antigen Receptor T Cells; T-Cell Exhaustion; Epigenetics; Metabolism; T-Cell Memory

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