TCR-T Modulation and Epigenetic Reprogramming for a Personalised Therapeutic Approach in Immunotherapy

Cancer immunotherapy holds immense potential for the future of medicine within the study of cancer therapeutics; however, most therapies are undermined by T-cell exhaustion and tumor immune evasion. T-cell exhaustion is caused by chronic antigen stimulation in the tumor microenvironment (TME), leading to dysfunctional epigenetically enforced states by transcription factors such as TOX and the NR4A family. Simultaneously, tumors evade the immune system by silencing MHC-1 molecules. Proposed is a synergistic approach that addresses these obstacles, involving the engineering of TCR-T cells for enhanced durability against the TME through CRISPR-Cas9-mediated knockout of exhaustion transcription factors, and the reprogramming of cancer cell transcriptomes using DNA methyltransferase (DNMTi) and histone deacetylase (HDACi) inhibitors. Furthermore, this review additionally incorporates: metabolic resistance, addressing the transfer of mitochondria from neurons to cancer cells, and enhancing oxidative phosphorylation (OXPHOS). These are proposed interventions for these obstacles with specific biomarkers (T-cell signatures, tumor epigenetic landscape, and tumor innervation density). By combining exhaustion-resistant T-cells with a reprogrammed tumor that is visible to the immune system, there is potential to overcome immune resistance and improve therapeutic outcomes for patients.