Applications of CRISPR Epigenome Editors in Tumor Immunology and Autoimmunity

Abstract

Over the past decade, CRISPR-Cas systems have become indispensable tools for genetic engineering and have been used in clinical trials for various diseases. Beyond genome editing, CRISPR-Cas systems can also be used for performing programmable epigenetic modifications. Recent efforts in enhancing CRISPR-based epigenome modifiers have yielded potent tools enabling targeted DNA methylation/demethylation capable of sustaining epigenetic memory through numerous cell divisions. Moreover, it has been understood that during chronic inflammatory states, including cancer, T cells encounter a state called T cell exhaustion that involves elevated inhibitory receptors (e.g., LAG-3, TIM3, PD-1, CD39) and reduced effector T cell-related protein levels (IFN-γ, granzyme B, and perforin). Importantly, epigenetic dysregulation has been identified as one of the key drivers of T cell exhaustion, and it remains one of the biggest obstacles in the field of immunotherapy and decreases the efficiency of chimeric antigen receptor T (CAR-T) cell therapy. Similarly, autoimmune diseases exhibit epigenetically dysfunctional regulatory T (Treg) cells. For instance, FOXP3 intronic regions, known as conserved noncoding sequences, display hypomethylation in healthy states but hypermethylation in pathological contexts. Therefore, the reversal of epigenetic dysregulation in cancer and autoimmune diseases using CRISPR-based epigenome modifiers has important therapeutic implications. In this review, we outline the progressive refinement of CRISPR-based epigenome modifiers and explore their potential therapeutic applications in tumor immunology and autoimmunity.

What is the role of microbial biotechnology and genetic engineering in medicine?

“…By rectifying disease‐causing mutations or introducing therapeutic genes, CRISPR‐Cas‐based gene therapies present promising pathways for developing effective treatments for genetic diseases such as cystic fibrosis, sickle cell disease, and Duchenne muscular dystrophy. Beyond genome editing, CRISPR‐Cas systems can also be employed for programmable epigenetic modifications, facilitating targeted DNA methylation or demethylation (Yahsi et al, 2024 ). Furthermore, using CRISPR–Cas‐based transactivation approaches (CRISPRa) with dCas proteins or antibody‐mediated recruitments, transcriptional activators can be recruited to genomic regulatory elements, enabling potent and versatile synthetic transcriptional control on genes of interest, such as dysregulated genes causing disease (Mahata et al, 2023 ).…”