T cell exhaustion: advances and challenges in revitalizing T cells

Research traces T cell exhaustion from prolonged antigen exposure and suppressive microenvironments to epigenetic and metabolic changes, and clinical work has progressed from identifying inhibitory receptors to using immune checkpoint inhibitors. The review highlights metabolic, cytokine and hypoxic drivers of exhaustion and calls for integrated molecular, metabolic and epigenetic approaches to inform future therapies.

T cell exhaustion is a state in which T cells progressively lose the ability to respond effectively to antigens, and it is increasingly recognised across chronic infections, cancer and several chronic diseases. Research has moved from identifying inhibitory receptors and core molecular pathways to clinical tools such as immune checkpoint blockade. Scientific attention now includes how metabolic stress, epigenetic programmes and the tissue environment shape exhaustion. The review summarises current drivers and outlines areas where more detailed mechanistic insight is needed. Key findings: - External environmental factors — prolonged antigen exposure, an immunosuppressive tumour or tissue microenvironment, accumulation of harmful metabolites, nutrient deprivation and hypoxia — are described as primary drivers that induce epigenetic, metabolic and functional changes in T cells. - Exhausted T cells commonly show upregulation of inhibitory receptors (for example PD‑1, CTLA‑4, TIM‑3), reduced proliferation and lowered cytokine production, and this phenotype is reported in chronic infections, cancer and a range of inflammatory and degenerative conditions. - Related but distinct states include anergy (an early, often more reversible hyporesponsive state with low IL‑2) and senescence (irreversible cell‑cycle arrest with markers such as CD57 and a proinflammatory SASP); these states have different implications for reversibility and therapy. - The tumour microenvironment is emphasised as a multifactorial cause of dysfunction through metabolic competition (glucose, glutamine, tryptophan), lipid accumulation and peroxidation, excess ROS, and immunosuppressive cytokines such as IL‑10 and TGF‑β, all of which can promote exhaustion. - Translational approaches now span checkpoint inhibitors, metabolic and epigenetic modulation, adoptive cell therapies and combination regimens, but progress is limited by cellular plasticity, TME heterogeneity and the current lack of robust biomarkers. Summary: T cell exhaustion reduces immune effectiveness in chronic infections, cancer and other diseases, and has been linked to durable epigenetic and metabolic reprogramming driven by sustained external stimuli. Clinical advances such as immune checkpoint blockade reflect these mechanistic insights, yet many molecular details remain unresolved. Future work described in the review centres on mapping regulatory networks, finding new molecular and metabolic targets, and integrating immunological, metabolic and epigenetic knowledge to inform therapies and biomarker development. Undetermined at this time.