Targeting T-cell exhaustion and tumour immune evasion: a review of emerging strategies.

Adoptive T-cell therapies and immune checkpoint blockade have produced durable remissions in selected malignancies, yet most patients still fail to achieve lasting benefit. Two convergent obstacles underlie much of this failure: T-cell exhaustion and tumour immune evasion. T-cell exhaustion arises from chronic antigen stimulation in the tumour microenvironment (TME) and spans a hierarchy from reversible, stem-like progenitor-exhausted cells to terminally exhausted cells with limited functional recovery, which is a transition epigenetically enforced by transcription factors such as TOX and the NR4A family. In parallel, tumours evade recognition by silencing antigen-presentation pathways, including MHC class I. This review discusses a complementary therapeutic strategy that addresses both obstacles: engineering T cells for greater durability in the TME through knockout of exhaustion-associated transcription factors, and reprogramming tumour cells with DNA methyltransferase (DNMTi) and histone deacetylase (HDACi) inhibitors to restore immunogenicity. We also consider emerging evidence that metabolic and neuro-immune features of the TME, including nerve-to-tumour mitochondrial transfer, may contribute to immune resistance in some tumour contexts. Importantly, we emphasise that most supporting evidence derives from CAR-T and murine systems, and that direct validation in TCR-engineered T-cell (TCR-T) platforms is still required. We further outline a personalised, biomarker-guided framework that integrates T-cell signatures, the epigenetic landscape of the tumour, and tumour innervation density to match combination therapy to the individual patient. Integrating exhaustion-resistant T cells with a reprogrammed, immunologically visible tumour may help address mechanisms of immune resistance and improve therapeutic outcomes.